1. 渐冻症治疗现状：现有手段的局限与挑战
1.1 渐冻症的病理与传统治疗困境
渐冻症，学名肌萎缩侧索硬化（ALS），是一种凶险的神经退行性疾病，它专门攻击我们大脑和脊髓里的“电线”——运动神经元。您可以把运动神经元想象成连接大脑和肌肉的信号线。一旦这些“信号线”发生退化、受损，大脑发出的指令就无法顺利传达到肌肉，肌肉自然就会逐渐萎缩、无力，甚至完全麻痹，就像被“冻”住了一样。这种退化是渐进的，不可逆转的。随着疾病进展，患者会逐渐丧失说话、吞咽、行走乃至呼吸的能力，最终往往因呼吸衰竭而离世 123。
面对渐冻症的无情侵袭，医学界一直在努力寻找有效的治疗方法。目前全球范围内获批用于治疗渐冻症的药物主要有利鲁唑（Riluzole）和依达拉奉（Edaravone）。利鲁唑是第一个获批的渐冻症药物，它的作用机制主要是抑制谷氨酸的释放，因为过多的谷氨酸被认为是导致运动神经元损伤的一个重要原因 4567。研究表明，利鲁唑能适度延长患者的生存期，大约能将中位生存期延长2到3个月 68。而依达拉奉则是一种抗氧化剂，它通过清除体内的自由基，减少氧化应激对神经元的损害，从而延缓疾病进展 4910。依达拉奉尤其对早期、疾病进展较快的患者显示出了一定的效果 1011。
然而，尽管这两种药物为患者带来了一线希望，但它们的疗效都比较有限，只能在一定程度上延缓疾病的进展，并不能彻底阻止神经元的退化，更无法逆转已发生的损伤 461213。患者仍然会面临肌肉进行性萎缩、全身无力、吞咽困难、构音障碍（说话不清楚）以及最致命的呼吸功能衰竭等问题 214。可以说，现有的治疗手段对于这种复杂的神经退行性疾病而言，仍是杯水车薪，远远不能满足患者的治疗需求。
1.2 治疗需求的迫切性：从诊断到预后的未满足需求
正是因为渐冻症的凶险和现有治疗手段的局限性，导致了巨大的未满足治疗需求，使得每位患者和家庭都面临着巨大的挑战。这种挑战首先体现在诊断的漫长与不确定上。渐冻症的初期症状往往不典型，容易与其他疾病混淆，加上疾病本身复杂的“异质性”——也就是说，每个患者发病部位、进展速度、具体表现都可能不太一样，这就像一场“捉迷藏”游戏，给医生诊断带来了很大的困难 1516。平均而言，从出现症状到最终确诊，患者可能要经历10到16个月的漫长等待 15。而这段时间，疾病却在悄无声息地继续进展，宝贵的干预窗口期也可能随之错过。
其次，传统疗法难以覆盖所有患者。我们前面提到的利鲁唑和依达拉奉，虽然有效，但并不是对所有患者都有效，也不是对所有患者都有显著效果。例如，依达拉奉主要对早期且进展较快的患者效果更明显，而对于晚期或进展缓慢的患者，其带来的益处可能就大打折扣。此外，并非所有患者都能耐受这些药物的副作用，这进一步限制了治疗的选择。
因此，对于渐冻症患者来说，他们最核心的诉求，不仅仅是“治愈”，更是希望能“减速”——减缓疾病进展的速度，让他们的身体功能能够多维持一段时间；同时，他们也渴望能够“改善生活质量”，即使疾病无法治愈，也希望能有尊严地生活，减少痛苦，保持与家人交流的能力，尽可能延长自主生活的时间 1718。这种对“减速”和“生活质量”的迫切需求，推动着科学家和医生们不断探索新的治疗路径，希望能够为渐冻症患者带来真正的改变。
2. 疾病修饰治疗：直击病因的新武器
2.1 超高剂量甲钴胺：早期患者功能衰退的“减速剂”
面对渐冻症这个“不速之客”，科学家们一直在寻找能够从根本上“修理”出问题神经元的药物，这类药物被称为“疾病修饰治疗”药物。其中，一种名为“超高剂量甲钴胺”的物质，近年来引起了广泛关注，它被视为早期渐冻症患者功能衰退的“减速剂” 19。您可能会觉得“甲钴胺”听起来有点耳熟，没错，它就是维生素B12的一种活性形式，日常生活中常用于营养神经。但这里我们说的“超高剂量”，可不是您平时在药店能买到的那种普通剂量，而是高达50毫克、每周两次的肌肉注射，剂量之高，远超常规补充维生素的范畴 20。
那么，这种“超高剂量甲钴胺”是如何发挥作用的呢？简单来说，它被认为通过多种途径来“滋养”和“保护”我们的运动神经元。有研究表明，超高剂量甲钴胺可以促进神经再生，并对受损的神经元起到保护作用 2122。它还能调节体内的同型半胱氨酸水平，这个同型半胱氨酸就像身体里的一个“小捣蛋”，过高时会对神经细胞造成伤害，而甲钴胺则能帮助它恢复正常，从而减少神经损伤 19。
日本的研究团队在过去十几年间，对超高剂量甲钴胺进行了深入的临床研究。最早在2007年，就有研究提示超高剂量甲钴胺能减缓渐冻症患者复合肌肉动作电位（可以理解为神经传导信号强弱的指标）的下降速度 21。在随后的一个长期II/III期临床试验（E761试验）中，研究人员发现，虽然在所有渐冻症患者中没有观察到显著的整体疗效，但如果在症状出现一年内就开始接受超高剂量甲钴胺治疗的早期患者，他们的生存期有所延长，疾病进展速度也明显减慢 23。
这些积极的早期信号促使研究人员开展了更具决定性的III期临床试验——JETALS（日本早期渐冻症超高剂量甲钴胺试验）2425。这项多中心、安慰剂对照、双盲的临床试验招募了130名在症状出现一年内的早期渐冻症患者。结果显示，在长达16周的随机治疗期间，接受超高剂量甲钴胺治疗的患者，其修订版渐冻症功能评定量表（ALSFRS-R，这是一个评估患者日常功能和疾病进展的常用工具）总分下降的速度，比接受安慰剂的患者显著减慢了1.97分 20。这意味着，超高剂量甲钴胺有效地“踩下了刹车”，延缓了患者日常功能（比如说话、吞咽、行走等）的衰退 20。
更重要的是，这项研究也证实了超高剂量甲钴胺在这一剂量下的安全性。在试验期间，两组患者（治疗组和安慰剂组）出现不良事件的比例相似，没有发现特别严重的副作用 20。
因此，超高剂量甲钴胺被认为是一种针对早期、病情进展速度中等的渐冻症患者的潜在疾病修饰疗法。它不是简单的维生素补充剂，而是一种具有明确作用机制的药物，为渐冻症的治疗带来了新的希望。
2.2 基因靶向疗法：SOD1突变患者的精准打击
在渐冻症的治疗探索中，基因靶向疗法无疑是近年来最令人兴奋的“新武器”之一。它不再是“眉毛胡子一把抓”，而是针对特定的基因突变，进行“精准打击”。这其中，最受瞩目的莫过于针对SOD1基因突变的疗法。
我们知道，大约有2%的渐冻症患者，他们的病因直接与SOD1基因突变有关 26。SOD1基因负责制造一种叫做超氧化物歧化酶1（Superoxide Dismutase 1）的蛋白质。这种蛋白质本来是身体的“清洁工”，负责清除细胞内有害的自由基，保护细胞不受损伤。但当SOD1基因发生突变时，它制造出来的SOD1蛋白质就变异了，变得有“毒性”，不仅不能好好工作，反而会损害运动神经元，导致渐冻症的发生 2728。这种“毒性增强”的效应，让科学家们看到了治疗的希望：如果能阻止这种有害的SOD1蛋白质产生，是不是就能阻止疾病的进展呢？
答案是肯定的，这就是“反义寡核苷酸”（Antisense Oligonucleotide, ASO）药物大显身手的地方。您可以把基因想象成一份建筑图纸，上面详细记录了如何建造SOD1蛋白质的指令。当这份图纸被细胞读取并复制成“信使RNA”（mRNA，可以理解为工地的施工指南）后，才能指导蛋白质的生产。托非生（Tofersen）就是一种专门设计的反义寡核苷酸药物 2728。它的作用，就好比一个“特殊剪刀”，能够精准地识别并“剪断”那些带有SOD1突变信息的“施工指南”（mRNA），从而阻止有毒SOD1蛋白质的合成 272930。简单来说，托非生通过“沉默”或“关闭”变异的SOD1基因，从源头上减少了有害蛋白质的产生。
这种“精准打击”的策略在临床试验中展现出了令人鼓舞的一面。在针对SOD1突变相关渐冻症患者进行的临床试验中，研究人员发现，使用托非生治疗后，患者脑脊液（环绕大脑和脊髓的液体）中SOD1蛋白质的浓度显著下降了，这意味着药物确实有效地减少了有害蛋白质的产生 293031。同时，患者血浆中的神经丝轻链（NfL）水平也大幅降低。神经丝轻链是神经元损伤后释放到血液中的一种生物标志物，它的减少，表明神经元损伤的程度有所减轻 262931。这就像是身体里的“神经元受损报警器”响得不那么频繁了，说明托非生在生物学层面上对渐冻症的病理过程产生了积极影响 3233。
然而，事情并非一帆风顺。尽管托非生在生物标志物上取得了显著进展，但在最初的III期临床试验（VALOR研究）中，托非生并未达到预设的主要临床终点——即在28周内显著改善患者的渐冻症功能评定量表（ALSFRS-R）评分 262932。ALSFRS-R评分是衡量患者日常功能（如说话、吞咽、行走等）进展的重要指标。这意味着，虽然有害蛋白质减少了，神经损伤的“报警器”不那么响了，但患者在实际功能上的改善却没有达到统计学上的显著差异。
这种“生物标志物改善”与“临床终点未达预期”之间的矛盾，引发了广泛的讨论。科学家们认为，这可能是因为渐冻症的复杂性，疾病的进展是一个漫长的过程，28周的观察期可能不足以充分体现药物的临床益处。此外，疾病的异质性、患者病情严重程度的差异等因素也可能影响结果。
但随后的开放标签扩展研究（Open-Label Extension, OLE）带来了新的希望。在这项研究中，早期开始接受托非生治疗的患者，相比于那些最初接受安慰剂、后期才转用托非生的患者，他们的疾病进展速度更慢，功能下降也更少 293133。这提示我们，越早开始治疗，效果可能越好。基于这些数据，美国食品药品监督管理局（FDA）在2023年4月加速批准了托非生（商品名：QALSODY）用于治疗SOD1突变相关的渐冻症，使其成为第一个获批的、针对特定基因突变的渐冻症疗法 2728343536。
目前，一项名为ATLAS的临床试验正在进行中，旨在探索托非生能否在临床症状出现之前，就延缓甚至预防SOD1突变携带者发病。这项研究将招募那些带有SOD1突变，并且血浆神经丝轻链水平已经升高（这可能预示着疾病即将发作）但尚未出现临床症状的人群 2637。如果成功，这将是渐冻症治疗领域的一个里程碑，有望将治疗窗口前移到疾病的“潜伏期”，从而从根本上改变疾病的自然进程。
基因靶向疗法，特别是以托非生为代表的反义寡核苷酸，为渐冻症的治疗开辟了全新的道路。虽然挑战犹存，例如药物的长期疗效和安全性仍需持续观察，并且部分患者在治疗过程中可能出现神经系统不良事件，如脊髓炎、神经根炎、无菌性脑膜炎和视乳头水肿等 38，但它为我们展示了“精准医疗”的巨大潜力，也激励着科学家们继续探索针对其他渐冻症相关基因（如C9orf72、FUS和ATXN2等）的靶向疗法 3940414243，最终目标是让更多的渐冻症患者能够受益于这种直击病因的“新武器”。
2.3 神经炎症调控：从机制到药物的转化突破
在渐冻症的复杂病理过程中，有一个“幕后黑手”正逐渐浮出水面，那就是神经炎症。我们可以把大脑和脊髓想象成一个精密的工厂，里面有各种各样的“工人”——神经元、星形胶质细胞、小胶质细胞等。正常情况下，这些“工人”各司其职，维持工厂的正常运转。但当工厂出现问题时（比如神经元受损），一些“特殊工人”——小胶质细胞和星形胶质细胞就会被“激活”，它们本意是想清理现场、修复损伤，但如果它们过度活跃，就会像失控的消防队员一样，不仅没有灭火，反而到处泼洒汽油，加剧了对神经元的损伤，这就是神经炎症的“促病作用” 4445。
神经炎症就像一场持续的“内战”，不断地损害运动神经元，加速疾病进展 46。因此，科学家们开始思考：如果能找到办法“安抚”这些过度活跃的“特殊工人”，或者减轻它们造成的“附带伤害”，是不是就能减缓渐冻症的进程呢？
正是在这样的背景下，一种名为牛磺熊去氧胆酸（TUDCA）的药物进入了研究人员的视线。TUDCA听起来有点陌生，但它其实是人体内一种天然存在的胆汁酸，主要作用是帮助消化。然而，令人惊喜的是，TUDCA还展现出了强大的神经保护作用 4748。
您可以把TUDCA想象成一个多才多艺的“和事佬”：
- 抑制细胞凋亡：在渐冻症中，受损的运动神经元会启动“自杀程序”（细胞凋亡）。TUDCA能有效地阻止这个“自杀程序”，给神经元争取更多生存时间 47。
- 减轻氧化应激：神经炎症常常伴随着大量的“自由基”（一种不稳定的分子），这些自由基就像“氧化剂”，会损害神经细胞。TUDCA能帮助细胞对抗这些“氧化剂”，减少氧化应激的伤害 47。
- 改善线粒体功能：线粒体是细胞的“能量工厂”。在渐冻症患者的神经元中，这些“能量工厂”常常出现故障。TUDCA有助于修复和保护线粒体，确保神经元有足够的能量来维持正常功能 49。
- 减少内质网应激：内质网是细胞内负责合成和折叠蛋白质的“车间”。当渐冻症中出现错误折叠的蛋白质时，“车间”就会不堪重负，产生“内质网应激”，最终导致细胞死亡。TUDCA能帮助“车间”减轻压力，恢复正常工作 4750。
- 抑制神经炎症：TUDCA具有抗神经炎症作用 47。
早期在动物模型中的研究，就已经展现了TUDCA的巨大潜力。在渐冻症的小鼠模型中，TUDCA能够显著地改善运动功能，延长小鼠的生存时间，并减少运动神经元的丢失 4750。
这些积极的动物实验结果，为TUDCA进入临床试验铺平了道路。在几项II期临床试验中，TUDCA作为渐冻症患者的辅助治疗（通常与利鲁唑联用），显示出了良好的耐受性和安全性。最令人鼓舞的是，这些研究观察到，与安慰剂组相比，接受TUDCA治疗的患者在ALSFRS-R评分（衡量日常功能的指标）的下降速度上有所减缓 4851。这意味着，TUDCA能够有效地“减速”疾病的进展，让患者的运动、吞咽、呼吸等功能维持更长的时间。
目前，一项名为TUDCA-ALS的III期临床试验正在欧洲多国进行，旨在进一步评估TUDCA作为利鲁唑的附加治疗在延缓ALS进展方面的有效性和安全性。这项研究计划招募320名患者，并使用“治疗反应”作为主要观察指标，即治疗期间ALSFRS-R评分下降速度至少提高20%的患者比例。这项研究的结果将对TUDCA在渐冻症治疗中的地位产生决定性影响 5253。
尽管在另一项结合了苯丁酸钠和TUDCA的药物AMX0035的III期临床试验中，未能达到主要终点，导致该药物最终被撤回 54，但这并不意味着TUDCA本身无效。因为AMX0035是一个复方药物，其结果不能完全等同于TUDCA单药的疗效。目前针对TUDCA单药的III期临床试验仍在进行中，其结果值得我们期待 5253。
可以说，神经炎症调控，以TUDCA为代表的药物，为渐冻症的治疗提供了一个全新的思路。通过“安抚”身体内的“失控卫兵”，并从多个层面保护神经元，TUDCA有望成为对抗渐冻症的又一有力武器。
3. 症状管理优化：提升生活质量的关键
渐冻症的治疗不仅仅是减缓疾病的进展，更重要的是帮助患者更好地应对疾病带来的各种挑战，提升他们的生活质量。因为即使是那些不能直接“治愈”疾病的干预措施，也能显著减轻患者的痛苦，让他们在病程中活得更有尊严，与家人有更多高质量的相处时间。其中，症状管理就是至关重要的一环，它关注的是疾病本身带来的各种不适，比如吞咽困难、呼吸问题、疼痛，以及这里我们要重点讨论的——流涎。
3.1 流涎控制：肉毒毒素与药物联合的新方案
渐冻症患者常常会面临一个让人尴尬又痛苦的问题——流涎（俗称“流口水”）。这并不是因为唾液分泌过多，而是由于疾病导致他们的吞咽肌肉无力，无法有效地吞咽口水，导致唾液在口腔积聚并溢出 55。正常人每天会分泌0.5到1.5升的唾液，当这些唾液无法正常吞咽时，就会给患者带来极大的困扰：不仅会弄湿衣物、损伤皮肤，影响社交，还会增加吸入性肺炎（口水呛入肺部）的风险，严重影响生活质量 55。
为了解决这个“甜蜜的负担”，医学界探索了多种方法，主要可以分为局部注射治疗和口服药物治疗两大类。
1. 肉毒毒素局部注射：精准“关闭”唾液腺
您可以把肉毒毒素想象成一个临时的“开关”。通过将它直接注射到分泌唾液的腺体（主要是腮腺和颌下腺），肉毒毒素能够抑制神经末梢释放一种叫做乙酰胆碱的物质，而这种物质正是刺激唾液腺分泌唾液的“信号” 5657。当这个“信号”被阻断后，唾液腺的分泌量就会显著减少，从而减轻流涎症状 58。
- 效果显著，持续时间长：多项研究表明，肉毒毒素（包括A型和B型）注射在减少唾液分泌和改善患者主观感受方面效果显著 555859。例如，一项针对20名渐冻症患者的研究发现，注射B型肉毒毒素后，患者报告的流涎症状有所改善，并且客观测量也显示唾液分泌量有所减少 55。通常，一次注射的效果可以维持1.5到6个月，让患者在这段时间内大大减轻流涎困扰 5960。最近在日本进行的一项III期临床试验也证实，A型肉毒毒素（incobotulinumtoxinA）能有效减少唾液分泌，改善流涎症状，且疗效可持续长达48周 61。另一项涉及187名患者的临床试验也显示，B型肉毒毒素（rimabotulinumtoxinB）注射后，唾液流速显著降低，患者整体情况得到改善，效果最快在注射后1周显现，并维持约13周 62。
- 副作用相对可控：肉毒毒素的副作用通常是局部性的，包括口干、吞咽困难和牙齿问题，但多为轻度至中度，且是可逆的 59606162。选择合适的剂量和精准的注射部位（通常在超声引导下进行），可以最大程度地减少副作用的发生 60。
- 局限性：肉毒毒素注射需要定期进行，并且可能存在抗体产生导致疗效下降的风险。
2. 口服药物：方便但需权衡副作用
除了局部注射，一些口服药物也可以帮助控制流涎：
- 右美沙芬/奎尼丁（DMQ）：这种复方药物原本主要用于治疗渐冻症患者的情绪不稳（假性延髓效应）。但研究发现，它对流涎也有一定的改善作用 5563。一项针对60名渐冻症患者的交叉研究显示，服用DMQ的患者在“神经系统研究延髓功能量表”（CNS-BFS）的流涎子量表评分上有所下降，表明流涎症状有所改善 5563。它的优势在于口服方便，但常见的副作用包括便秘、腹泻、恶心和头晕 55。
- 其他抗胆碱能药物：像东莨菪碱贴片（scopolamine）等传统抗胆碱能药物也可以减少唾液分泌，但其全身性的副作用（如口干、视力模糊、便秘、认知障碍等）往往会限制它们在渐冻症患者中的使用，特别是在老年患者中 55。
3. 放射治疗：长效但需谨慎
除了药物和注射，放射治疗也是一种选择。通过对唾液腺进行局部放疗，可以永久性地破坏部分腺体组织，从而减少唾液分泌。一项观察性研究显示，在渐冻症患者中，放疗在1个月后能让80%的患者感到改善，6个月后仍有43%的患者感到改善，其中电子束放疗效果更佳 64。然而，放射治疗可能伴随口干、味觉改变等副作用，且作为一种不可逆的治疗方式，需要谨慎评估其风险与收益。
个体化选择策略：没有一劳永逸的方案
面对这些多样化的治疗方案，关键在于个体化。没有一种方案是适用于所有渐冻症患者的“万能药”。医生会根据患者的病情严重程度、其他症状、身体状况、药物耐受性以及个人意愿，综合评估后制定最佳的治疗策略：
- 对于流涎症状较重，且希望能获得较长效缓解的患者，肉毒毒素注射可能是一个很好的选择。
- 如果患者同时伴有情绪不稳，DMQ可能在改善流涎的同时兼顾情绪问题。
- 对于那些无法耐受注射或口服药物副作用的患者，或者其他治疗效果不佳时，放射治疗可以在严格评估后作为一种选择。
总而言之，控制流涎是渐冻症综合管理中不可或缺的一环，它不仅能提升患者的生理舒适度，更能维护他们的尊严和社交能力，从而显著改善他们的生活质量。
3.2 呼吸与营养支持：从被动应对到主动干预
渐冻症最致命的威胁之一就是呼吸肌无力，最终导致呼吸衰竭 6566。想象一下，呼吸就像我们身体最基本的“发动机”，它需要胸部和膈肌的肌肉有节奏地收缩和舒张来完成。当这些肌肉因为渐冻症而逐渐萎缩、无力时，“发动机”的动力就会不足，吸入的氧气越来越少，呼出的二氧化碳越来越多，这就是呼吸功能不全。早期，这可能表现为夜间睡眠不佳、白天疲劳、头痛等不明显的症状，但随着病情进展，呼吸困难会越来越严重，最终威胁生命 65。
传统上，对于渐冻症的呼吸支持往往是被动的，等到患者呼吸明显困难时才开始介入。但现在，医学界越来越强调主动干预的重要性，这包括了先进的呼吸支持技术和积极的营养管理。
1. 非侵入性通气（NIV）：呼吸的“助推器”
非侵入性通气，俗称“无创呼吸机”，就是通过面罩或鼻罩将空气（或混合有氧气的空气）送入肺部，辅助患者呼吸。它就像一个体外的“助推器”，帮助疲惫的呼吸肌完成工作，确保身体获得足够的氧气，排出多余的二氧化碳。
- 延长生存期，改善生活质量：多项研究一致表明，对于没有严重延髓功能障碍（即吞咽和说话能力尚可）的渐冻症患者，早期使用NIV能够显著延长生存期，同时还能改善或维持他们的生活质量 666768。有研究显示，NIV可以将患者的中位生存期延长205天（约7个月），这比现有许多药物的延缓效果都要显著 6667。即使是那些延髓功能较差的患者，NIV也能改善他们的睡眠相关症状，尽管对生存期的延长效果不那么明显 6667。
- “早”字是关键：最新的研究趋势是提倡更早地介入NIV。过去，通常建议在患者用力肺活量（FVC，衡量肺功能的重要指标）下降到预测值的50%以下时才开始使用NIV。但现在有研究表明，如果能在FVC下降到75%时就提前开始使用NIV，可能更有益处 69。一项多中心随机对照试验发现，早期使用NIV虽然未能达到统计学意义上的显著延长生存期，但它能延缓呼吸肌肉力量的下降，并减少不良事件的发生，患者对早期使用NIV的耐受性和依从性也很好，并没有影响睡眠质量 69。这说明，就像给身体的“发动机”提前加油保养一样，早期介入NIV可以更好地保护呼吸功能，延缓其衰退。
- 智能呼吸机与咳嗽辅助技术：现代的呼吸机技术不断发展，能够更好地适应患者的呼吸需求，提高舒适度和依从性。此外，咳嗽辅助技术也变得越来越重要。渐冻症患者不仅呼吸肌无力，咳嗽肌也无力，难以有效咳出痰液，容易引起肺部感染。咳嗽辅助机能模拟强力咳嗽，帮助患者清除呼吸道分泌物，进一步保障呼吸健康 6870。
2. 营养支持：维持生命的“燃料”
渐冻症患者由于肌肉萎缩、吞咽困难、能量消耗增加等原因，很容易出现体重下降和营养不良 717273。而体重下降与较差的生存预后密切相关，体质指数（BMI）较低的患者死亡风险更高 727475。因此，积极的营养支持，就像为身体提供充足的“燃料”，对于维持患者的生命活动和延缓疾病进展至关重要。
- 高热量饮食与体重维持：研究表明，维持或增加体重，特别是通过高热量饮食，可能有助于延长渐冻症患者的生存期 727475。这并不是简单地多吃，而是需要专业的营养师评估，根据患者的个体情况制定个性化的饮食方案。这个方案可能包括使用口服营养补充剂等，同时辅以食物优先的方法来达到个体化的卡路里目标 747576。一项正在进行的临床试验（OptiCALS）旨在评估早期高热量饮食对渐冻症患者功能预后的影响，其结果值得期待 74。
- 吞咽功能训练与胃造瘘术：渐冻症患者的吞咽困难（吞咽障碍）是导致营养不良的主要原因之一。这就像吃饭的“通道”不畅，食物难以安全进入胃部。
从被动等到出现问题再干预，到主动评估、早期介入，呼吸与营养支持的理念正在发生转变。这就像对待一辆逐渐老化的汽车，不再是等它抛锚了才去修，而是定期检查、提前保养，及时更换磨损的零件，甚至升级更好的配件，只为让它跑得更久、更稳，最大限度地提升渐冻症患者的生活质量和生存时间。
4. 非药物干预：综合管理的新探索
除了药物治疗和各种支持性干预，渐冻症的综合管理还包括一系列非药物干预措施。这些措施虽然不能直接治愈疾病，但却能在很大程度上改善患者的身体功能、心理状态，提升他们的生活质量。它们像是一张细密的防护网，从各个方面支撑着患者，帮助他们更好地应对疾病带来的挑战。其中，运动疗法和姑息治疗是两个重要的组成部分。
4.1 运动疗法：科学强度下的功能维持
长期以来，对于渐冻症患者是否应该进行运动，一直存在争议。过去人们担心，运动可能会加速肌肉损伤，反而对患者不利。然而，随着研究的深入，这种观念正在被纠正。现在越来越多的证据表明，科学、适度的运动疗法不仅安全，而且能够帮助渐冻症患者维持肌肉力量，改善功能，甚至对心理状态也有积极的影响 80818283。
您可以把运动疗法想象成给渐冻症患者的身体做“保养”。虽然发动机的零件可能正在老化，但良好的保养仍然能让它运行得更顺畅，减少不必要的磨损。
适度康复训练，维持肌肉功能：多项系统评价和荟萃分析（对大量研究进行总结和分析）指出，适度的康复训练可以安全地应用于渐冻症患者 80818384。这些训练包括：
- 抗阻运动（力量训练）：通过使用轻量器械、弹力带或自身体重进行肌肉锻炼，可以帮助患者在一定程度上维持现有的肌肉力量，减缓肌肉萎缩的速度 85。一项针对早期渐冻症患者的研究发现，长期的抗阻训练能够改善患者的肌肉力量和平衡能力，并且没有加重疲劳或引起其他不良反应 85。
- 有氧运动：例如，在力所能及的范围内进行散步、水上运动或使用卧式自行车等，可以改善心肺功能，提高耐力，从而减轻疲劳感，改善整体功能 8285。
- 柔韧性训练（拉伸）：渐冻症患者常常会因为肌肉萎缩和痉挛导致关节僵硬、活动受限。规律的拉伸运动可以帮助他们保持关节的活动度，减少疼痛和僵硬感 83。
- 平衡训练：针对平衡能力的训练有助于提高患者的行动安全性 83。
改善功能评分，延缓功能衰退：有研究表明，接受治疗性体育锻炼的渐冻症患者，其ALSFRS-R评分（功能评估量表）的下降速度相比对照组有所减缓 80。这意味着，通过运动，患者在日常活动（如穿衣、吃饭、行走等）上的独立性可以维持更长的时间。一项荟萃分析也指出，运动能显著改善患者的功能能力和肺功能 8182。另一项研究则发现，为期12周的有氧和力量训练相结合的方案，在改善呼吸功能、活动能力和ALSFRS-R评分方面，明显优于单独进行柔韧性训练的对照组 85。
积极影响心理状态：除了生理上的益处，运动对患者的心理健康也大有裨益。一项试点研究甚至发现，动物辅助治疗（特别是狗辅助理疗）对渐冻症患者的运动功能和心理状态都有显著的积极影响。研究中，患有渐冻症的患者与治疗犬互动进行康复训练，结果显示他们在运动量表评分和焦虑抑郁量表评分上都有显著改善，效果甚至优于传统理疗 8687。这说明，运动与趣味性结合，更能激发患者的积极性，可能也有助于缓解焦虑和抑郁，提升自我效能感，让他们感觉更能掌控自己的身体，从而提高生活质量。
“不过度消耗”的原则：尽管运动有益，但对于渐冻症患者而言，“度”至关重要。运动的首要原则是“安全和不过度消耗”。过度运动可能导致肌肉疲劳加剧，甚至加速损伤。因此，运动方案必须是个性化的，由专业的物理治疗师或康复医生根据患者的病情阶段、肌肉力量、疲劳程度和耐受性来制定和调整 8388。
- 监测疲劳：患者在运动过程中和运动后应密切关注自身疲劳水平。
- 避免肌肉痉挛和疼痛：如果运动导致肌肉痉挛或疼痛加剧，应立即停止并调整方案。
- 循序渐进：运动强度和时间应逐步增加，而不是一蹴而就。
- 保持能量储备：运动的目的是为了维持功能，而不是为了追求肌肉生长或极限挑战。
总而言之，在专业指导下进行的适度运动，能够帮助渐冻症患者在功能上“减速”，在心理上“加油”，是综合管理中不可或缺的一部分。
4.2 姑息治疗：从“临终关怀”到全程照护的转变
在许多人的传统观念里，“姑息治疗”常常与“临终关怀”画上等号，认为只有在疾病晚期、治疗无望时才需要介入。然而，对于渐冻症这种不可治愈且进行性恶化的疾病来说，这种观念亟需转变。现代医学提倡的姑息治疗，是一种从诊断之初就应早期介入，并贯穿疾病全程的综合照护，它不仅仅是“临终关怀”，更是一种“全程照护”，旨在最大程度地提升患者及其家属的生活质量 186589。
您可以把姑息治疗想象成一艘在风浪中航行的船，疾病是汹涌的波涛。药物治疗可能只是修理船体，减缓漏水，而姑息治疗则像船上的高级导航系统和船员，它不仅能帮助船员应对航行中的各种困难（症状管理），还能为乘客提供舒适的环境（心理支持），更重要的是，它能帮助乘客和船长提前规划航线，甚至在风暴来临前就做好最坏的打算（预立医疗照护计划）。
1. 早期介入：将姑息治疗融入日常照护
将姑息治疗早期引入渐冻症的诊疗过程至关重要 18。当患者被诊断出渐冻症时，他们和家人都会感到巨大的冲击和无助。此时，姑息治疗团队的介入，可以帮助他们更好地理解疾病，应对心理打击，并提前规划未来的照护。
- 心理疏导与情感支持：渐冻症患者常伴有心理问题 90。姑息治疗团队中的心理医生或受过专业训练的护士，可以通过倾听、共情和专业的心理干预，帮助患者及家属缓解情绪，适应疾病带来的变化。他们会告诉患者，感到悲伤、愤怒是正常的，并帮助他们找到应对机制，重建生活的意义。
- 症状管理：减轻痛苦，提高舒适度：姑息治疗的核心之一是积极管理疾病带来的各种不适症状，如疼痛、疲劳、肌肉痉挛、吞咽困难、呼吸困难等 188991。例如，对于疼痛，医生会根据患者具体情况选择合适的止痛药；对于严重的唾液过多，会使用肉毒毒素注射或口服药物进行干预（如前文所述）。目标是让患者尽可能地舒适，减少身体上的痛苦。
- 沟通技巧：帮助患者面对疾病：医疗专业人员需要具备良好的沟通技巧，帮助患者理解疾病的进展，并讨论关于生命终点的议题 92。这需要耐心、同情心和专业的知识，以确保患者在理解的基础上做出符合自己意愿的决定。
2. 预立医疗照护计划（ACP）：掌控自己的未来
渐冻症的一个残酷现实是，随着疾病的进展，患者可能会失去说话和自主做决定的能力。因此，预立医疗照护计划（Advance Care Planning, ACP）变得尤为重要 93949596。ACP让患者在有能力沟通时，提前表达自己对未来医疗选择的意愿，包括是否接受气管切开术和有创通气（即使用呼吸机）、是否接受胃造瘘管喂养、希望在何处离世等 929395。
- 尊重患者意愿：ACP确保患者在疾病晚期，即使无法表达，也能按照自己的价值观和意愿获得照护，而不是被动地接受医疗干预 1893。研究表明，通过ACP，临床团队对患者意愿的理解程度显著提高 94。
- 减轻家属负担：当患者事先明确了意愿，家属在面临艰难的医疗决策时，可以避免巨大的心理压力和决策冲突，因为他们知道是在遵循患者本人的选择 93。
- 尽管重要，但普及率仍不高：尽管ACP对渐冻症患者至关重要，但目前的统计数据显示，只有不到三分之一的渐冻症患者完成了ACP文件，而完成“维持生命治疗医嘱”（POLST）等具体文件的比例更低 9798。这表明，在推广ACP方面仍有很大的努力空间。研究也发现，在诊断后的几个月内，许多患者就有了关于预立指示和生命终期治疗选择的思考 95。因此，医护人员应主动引导并帮助患者完成ACP。
3. 多学科团队协作：全面的支持网络
姑息治疗的实践离不开一个紧密协作的多学科团队。这个团队可能包括神经科医生、姑息治疗专家、心理医生、康复治疗师（物理治疗师、职业治疗师、言语治疗师）、营养师、社会工作者和护理人员等 18659091。
- 无缝衔接的照护：多学科团队的优势在于能够提供全面、协调一致的照护。例如，神经科医生专注于疾病的诊断和治疗进展，康复治疗师帮助患者维持功能，营养师确保患者获得充足营养，而姑息治疗专家则专注于症状管理、心理支持和ACP的引导。
- 早期协作的益处：理想情况下，姑息治疗团队应与渐冻症诊疗中心早期建立合作，共同为患者提供照护，而不是等到疾病晚期才介入 9299。这种早期协作能够确保患者从疾病的早期阶段就获得全方位的支持，并在疾病进展过程中不断调整照护方案，满足不断变化的身体和心理需求。
- 家属支持：姑息治疗也延伸到家属身上，为他们提供心理支持、照护培训和哀伤辅导，帮助他们应对患者疾病带来的挑战，并在患者离世后平稳过渡 65100。
总而言之，姑息治疗已经从传统的“临终关怀”演变为一种贯穿疾病全程的综合管理策略。它不仅仅是对患者身体痛苦的缓解，更是对他们心理、情感和社会需求的全面关怀，让渐冻症患者在疾病面前，依然能拥有尊严、舒适和高质量的生活。
5. 未来方向：从实验室到临床的转化之路
5.1 生物标志物与精准分型：治疗方案的“导航仪”
在渐冻症的治疗征程中，我们就像是在一片迷雾中航行，疾病的复杂性和异质性让前路充满了不确定。然而，生物标志物和精准分型的出现，正如同“导航仪”一般，为我们指明了方向，帮助医生更早地诊断疾病，更准确地预测疾病进程，并为患者量身定制最合适的治疗方案 1101102。
1. 生物标志物：疾病的“晴雨表”
您可以把生物标志物想象成身体里的一些“信号灯”或者“晴雨表”，它们的变化能反映出疾病的发生、发展、严重程度以及治疗效果。在渐冻症领域，最受关注的生物标志物当属神经丝轻链（Neurofilament Light chain, NfL）。
- 神经丝轻链（NfL）：神经元损伤的“报警器”
- NfL是什么？ 神经丝是神经元内部骨架的重要组成部分，就像钢筋支撑着建筑的结构。当神经元受损时，这些神经丝就会分解，其中的轻链部分（NfL）会释放到脑脊液和血液中 103104。因此，血液或脑脊液中NfL水平的升高，就像是神经元受损的“报警器”被拉响了。
- 诊断与疾病进展监测：渐冻症患者的NfL水平通常显著高于健康人，这使得NfL成为诊断渐冻症的潜在工具 103104105。更重要的是，NfL水平与疾病的进展速度密切相关。NfL水平越高，通常意味着神经元损伤越严重，疾病进展可能越快 105106。这就好比“晴雨表”的读数越高，预示着“风暴”可能越猛烈。因此，医生可以通过定期监测NfL水平，来评估疾病的进展情况，甚至预测患者的生存期 1104。
- 疗效评估：在新的治疗方案（尤其是疾病修饰疗法）的临床试验中，NfL被广泛用作评估药物疗效的重要指标。例如，在针对SOD1突变渐冻症的托非生（Tofersen）治疗中，NfL水平的显著下降被视为药物有效减少神经元损伤的有力证据，即使在临床功能改善不明显的情况下，NfL的变化也为药物的审批提供了支持 31105106。这就好比“导航仪”显示，尽管船速还没明显加快，但引擎的磨损率已经显著降低了。
- 挑战与未来：尽管NfL的潜力巨大，但将其广泛应用于临床仍面临一些挑战。例如，不同的检测方法可能导致NfL读数存在差异，需要进一步的标准化 104107。此外，NfL升高并非渐冻症特有，其他神经系统疾病（如多发性硬化、阿尔茨海默病等）也可能导致NfL升高，因此需要结合临床表现和其他检查进行综合判断 103104。
2. 基因分型：量体裁衣的“定制治疗”
渐冻症并非单一疾病，而是由多种基因和环境因素共同作用的复杂疾病。大约10%的渐冻症患者有家族史，被称为家族性渐冻症，其余90%则为散发性渐冻症 108。然而，即使是散发性渐冻症患者，也有相当一部分被发现存在与疾病相关的基因突变 109。这表明，基因分型对于理解疾病异质性、指导靶向治疗至关重要。
- C9orf72基因突变：最常见的遗传病因
- 普遍性：
C9orf72基因上的特定重复序列扩增是渐冻症最常见的遗传病因之一，在家族性渐冻症中约占40%至50% 108。在散发性渐冻症患者中，C9orf72突变在某些地区也占有一定比例，例如挪威的研究显示为6.8% 109。 - 对靶向治疗的指导意义：了解患者是否携带
C9orf72突变，对于开发和选择靶向治疗方案具有重要意义。就像SOD1突变催生了托非生一样，科学家们也在积极开发针对C9orf72突变的反义寡核苷酸药物，旨在“沉默”或“关闭”这个异常基因，阻止其产生有害的蛋白质和RNA，从而阻止神经元损伤 110。一些早期研究已经显示出希望，但这方面的临床试验仍在进行中。 - 疾病的“多样性”：值得注意的是，
C9orf72突变不仅与渐冻症相关，还可能导致额颞叶痴呆（FTD）或其他神经系统疾病，这进一步凸显了基因分型在精准诊断和治疗中的作用 111。
- 普遍性：
- SOD1基因突变：托非生的“靶点”
- 我们前面已经详细介绍了
SOD1基因突变与托非生治疗的故事。SOD1突变约占家族性渐冻症的10%到20% 108。对患者进行SOD1基因检测，能够明确他们是否适用于托非生治疗，实现了真正的“精准打击”。
- 我们前面已经详细介绍了
- 其他基因突变：除了
C9orf72和SOD1，还有FUS、TARDBP、TBK1、SQSTM1等多种基因被发现与渐冻症有关 109112113。随着基因测序技术的发展，对渐冻症患者进行全面的基因检测变得越来越可行，这将有助于揭示疾病的遗传背景，并可能发现新的药物靶点。例如，SQSTM1基因突变可能通过影响细胞自噬和炎症通路来导致疾病，这为开发针对这些通路的个性化治疗提供了线索 112。
总而言之，生物标志物和基因分型是精准医疗在渐冻症领域取得进展的关键。它们不仅能帮助医生更早、更准确地诊断疾病，还能将患者进行精细化分层，为他们找到最匹配的治疗方案，让渐冻症的治疗从“大海捞针”走向“精准导航”。
5.2 前沿技术：干细胞与基因编辑的潜在突破
在与渐冻症的较量中，除了现有药物和生物标志物的突破，科学家们还将目光投向了更具颠覆性的前沿技术：干细胞治疗和基因编辑。这些技术如同科幻小说中的场景，正在实验室里逐步变为现实，为渐冻症患者带来了未来治愈的无限遐想。
1. 干细胞治疗：身体的“修复大师”
干细胞，尤其是间充质干细胞（Mesenchymal Stem Cells, MSCs），被誉为我们身体里的“修复大师”。它们就像是“多功能工人”，不仅能够自我更新，还能分化成多种细胞类型，更重要的是，它们还能分泌各种营养物质、生长因子，并调节免疫反应，为受损组织创造一个更好的修复环境 114115。在渐冻症的治疗中，干细胞疗法主要探索以下几个方向：
神经保护和微环境改善：渐冻症患者的运动神经元之所以退化，除了基因问题，也与神经元周围的微环境“变坏”有关。受损的胶质细胞、炎症因子等都会加速神经元的死亡。间充质干细胞就像一个“万能清洁队”，它们能够：
临床进展：目前，全球范围内已经开展了多项使用间充质干细胞治疗渐冻症的临床试验 117。这些试验通常通过将干细胞注射到患者的脊髓液（鞘内注射）或直接注射到肌肉中。早期研究显示，间充质干细胞治疗是相对安全的，且部分患者在功能评分上有所改善，疾病进展速度减缓 117118。例如，有研究显示，自体骨髓间充质干细胞联合利鲁唑治疗，在4到6个月后可能轻微减少患者的功能障碍 118。此外，神经干细胞/祖细胞（Neural Stem/Progenitor Cells, NSPCs）的移植也被认为能够改善渐冻症动物模型的身体功能，并延缓患者的疾病进展 119。
挑战与优化：尽管前景光明，干细胞治疗仍面临诸多挑战。
2. 基因编辑：修正生命的“错别字”
如果说干细胞是“修复大师”，那么基因编辑技术，特别是CRISPR-Cas9系统，则更像是可以修改生命“蓝图”的“基因手术刀” 41121122。它能精准地找到基因中的“错别字”并进行修正，从而从根源上消除疾病的病因。对于渐冻症，基因编辑技术主要聚焦于修正那些导致疾病的致病基因突变：
CRISPR-Cas9技术：这种技术能够像一把“分子剪刀”，精准地剪掉DNA链上特定的“错误”片段，然后细胞会尝试修复这个断裂，从而修正基因突变或者使致病基因失活 121123。
针对FUS突变：
FUS基因是另一个与家族性渐冻症相关的基因。当FUS基因发生突变时，会产生有毒的FUS蛋白，导致神经元损伤。研究人员正在探索使用CRISPR-Cas9技术，通过基因编辑来修正FUS基因的突变，或者降低其异常表达，从而阻止FUS蛋白的毒性作用 39123。虽然目前主要还在动物模型和细胞系研究阶段，但已经展现出巨大的潜力。挑战与展望：基因编辑技术虽然强大，但要真正应用于渐冻症患者，仍有许多难关需要攻克：
总而言之，干细胞治疗和基因编辑技术代表了渐冻症治疗的未来方向。它们正在将我们对疾病的理解从“症状管理”提升到“根本治疗”的层面。虽然离真正应用于临床还有一段距离，但这些前沿技术的不断突破，无疑为那些与渐冻症抗争的患者们带来了最深切的希望。
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参考文献
1Current State and Future Directions in the Diagnosis of Amyotrophic Lateral Sclerosis.PubMed
Maximilian Vidovic, Lars Hendrik Müschen, Svenja Brakemeier, et al.
Cells. 2023 Feb 24;12(5):736. doi: 10.3390/cells12050736.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurons, resulting in progressive weakness of all voluntary muscles and eventual respiratory failure. Non-motor symptoms, such as cognitive and behavioral changes, frequently occur over the course of the disease. Considering its poor prognosis with a median survival time of 2 to 4 years and limited causal treatment options, an early diagnosis of ALS plays an essential role. In the past, diagnosis has primarily been determined by clinical findings supported by electrophysiological and laboratory measurements. To increase diagnostic accuracy, reduce diagnostic delay, optimize stratification in clinical trials and provide quantitative monitoring of disease progression and treatment responsivity, research on disease-specific and feasible fluid biomarkers, such as neurofilaments, has been intensely pursued. Advances in imaging techniques have additionally yielded diagnostic benefits. Growing perception and greater availability of genetic testing facilitate early identification of pathogenic ALS-related gene mutations, predictive testing and access to novel therapeutic agents in clinical trials addressing disease-modified therapies before the advent of the first clinical symptoms. Lately, personalized survival prediction models have been proposed to offer a more detailed disclosure of the prognosis for the patient. In this review, the established procedures and future directions in the diagnostics of ALS are summarized to serve as a practical guideline and to improve the diagnostic pathway of this burdensome disease.
2Pathophysiology, Clinical Heterogeneity, and Therapeutic Advances in Amyotrophic Lateral Sclerosis: A Comprehensive Review of Molecular Mechanisms, Diagnostic Challenges, and Multidisciplinary Management Strategies.PubMed
María González-Sánchez, María Jesús Ramírez-Expósito, José Manuel Martínez-Martos
Life (Basel). 2025 Apr 14;15(4):647. doi: 10.3390/life15040647.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons, leading to muscle atrophy, paralysis, and respiratory failure. This comprehensive review synthesizes the current knowledge on ALS pathophysiology, clinical heterogeneity, diagnostic frameworks, and evolving therapeutic strategies. Mechanistically, ALS arises from complex interactions between genetic mutations (e.g., in , , (TDP-43), and ) and dysregulated cellular pathways, including impaired RNA metabolism, protein misfolding, nucleocytoplasmic transport defects, and prion-like propagation of toxic aggregates. Phenotypic heterogeneity, manifesting as bulbar-, spinal-, or respiratory-onset variants, complicates its early diagnosis, which thus necessitates the rigorous application of the revised El Escorial criteria and emerging biomarkers such as neurofilament light chain. Clinically, ALS intersects with frontotemporal dementia (FTD) in up to 50% of the cases, driven by shared TDP-43 pathology and hexanucleotide expansions. Epidemiological studies have revealed a lifetime risk of 1:350, with male predominance (1.5:1) and peak onset between 50 and 70 years. Disease progression varies widely, with a median survival of 2-4 years post-diagnosis, underscoring the urgency for early intervention. Approved therapies, including riluzole (glutamate modulation), edaravone (antioxidant), and tofersen (antisense oligonucleotide), offer modest survival benefits, while dextromethorphan/quinidine alleviates the pseudobulbar affect. Non-pharmacological treatment advances, such as non-invasive ventilation (NIV), prolong survival by 13 months and improve quality of life, particularly in bulb-involved patients. Multidisciplinary care-integrating physical therapy, respiratory support, nutritional management, and cognitive assessments-is critical to addressing motor and non-motor symptoms (e.g., dysphagia, spasticity, sleep disturbances). Emerging therapies show promise in preclinical models. However, challenges persist in translating genetic insights into universally effective treatments. Ethical considerations, including euthanasia and end-of-life decision-making, further highlight the need for patient-centered communication and palliative strategies.
3Amyotrophic lateral sclerosis.PubMed
C E Jackson, W W Bryan
Semin Neurol. 1998;18(1):27-39. doi: 10.1055/s-2008-1040859.
Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with evidence of both anterior horn cell and corticospinal tract degeneration. The incidence of ALS is 1 to 2.5 cases per 100,000 population and the disease occurs primarily in adult life. The etiology of sporadic ALS remains unknown, although 5 to 10% of cases are familial. The diagnosis of ALS requires the presence of both upper and lower motor neuron findings and progressive motor dysfunction. Several theories regarding the pathogenesis of ALS have emerged including glutamate excitotoxicity, free radical oxidative stress, neurofilament accumulation, and autoimmunity. Clinical trials involving antiglutamate agents, antioxidants, immunosuppressants, and growth factors have shown no substantial benefit in slowing progression, with death usually occurring 2 to 5 years following the onset of symptoms. The management of ALS patients requires a multidisciplinary team that can provide the numerous medical and physical interventions necessary to treat weakness and fatigue, bulbar dysfunction, spasticity and pain, depression, and respiratory failure.
4Riluzole and edaravone: A tale of two amyotrophic lateral sclerosis drugs.PubMed
Manoj Kumar Jaiswal
Med Res Rev. 2019 Mar;39(2):733-748. doi: 10.1002/med.21528. Epub 2018 Aug 12.
Over the past decades, a multitude of experimental drugs have been shown to delay disease progression in preclinical animal models of amyotrophic lateral sclerosis (ALS) but failed to show efficacy in human clinical trials or are still waiting for approval under Phase I-III trials. Riluzole, a glutamatergic neurotransmission inhibitor, is the only drug approved by the USA Food and Drug Administration for ALS treatment with modest benefits on survival. Recently, an antioxidant drug, edaravone, developed by Mitsubishi Tanabe Pharma was found to be effective in halting ALS progression during early stages. The newly approved drug edaravone is a force multiplier for ALS treatment. This short report provides an overview of the two drugs that have been approved for ALS treatment and highlights an update on the timeline of drug development, how clinical trials were done, the outcome of these trials, primary endpoint, mechanism of actions, dosing information, administration, side effects, and storage procedures. Moreover, we also discussed the pressing issues and challenges of ALS clinical trials and drug developments as well as future outlook.
5The pharmacology and mechanism of action of riluzole.PubMed
A Doble
Neurology. 1996 Dec;47(6 Suppl 4):S233-41. doi: 10.1212/wnl.47.6_suppl_4.233s.
The excitotoxic hypothesis of neurodegeneration has stimulated much interest in the possibility of using compounds that will block excitotoxic processes to treat neurologic disorders. Riluzole is a neuroprotective drug that blocks glutamatergic neurotransmission in the CNS. Riluzole inhibits the release of glutamic acid from cultured neurons, from brain slices, and from corticostriatal neurons in vivo. It is thought these effects may be partly due to inactivation of voltage-dependent sodium channels on glutamatergic nerve terminals, as well as activation of a G-protein-dependent signal transduction process. Riluzole also blocks some of the postsynaptic effects of glutamic acid by noncompetitive blockade of N-methyl-D-aspartate (NMDA) receptors. In vivo, riluzole has neuroprotective, anticonvulsant, and sedative properties. In a rodent model of transient global cerebral ischemia, a complete suppression of the ischemia-evoked surge in glutamic acid release has been observed. In vitro, riluzole protects cultured neurons from anoxic damage, from the toxic effects of glutamic-acid-uptake inhibitors, and from the toxic factor in the CSF of patients with amyotrophic lateral sclerosis.
6Riluzole for the treatment of amyotrophic lateral sclerosis.PubMed
Yuji Saitoh, Yuji Takahashi
Neurodegener Dis Manag. 2020 Dec;10(6):343-355. doi: 10.2217/nmt-2020-0033. Epub 2020 Aug 27.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the death of motor neurons. Riluzole is a benzothiazole derivative that blocks glutamatergic neurotransmission in the CNS, which is thought to exert neuroprotective effects. Riluzole was approved by the US FDA in 1995 as the first drug to treat ALS. Although riluzole is generally safe and well tolerated in clinical practice, its efficacy in ALS is modest, prolonging tracheostomy-free survival by only 2-3 months. In this article, we will first provide an overview of the ALS field, followed by a discussion of riluzole regarding its physical properties; pharmacology; clinical efficacy in ALS; safety and tolerability; and recommended administration.
7A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group.PubMed
G Bensimon, L Lacomblez, V Meininger
N Engl J Med. 1994 Mar 3;330(9):585-91. doi: 10.1056/NEJM199403033300901.
BACKGROUND: Amyotrophic lateral sclerosis is a progressive motor neuron disease for which there is no adequate treatment. Some research suggests that the excitatory amino acid neurotransmitter glutamate may be involved in the pathogenesis. METHODS: To evaluate the efficacy and safety of the antiglutamate agent riluzole, we conducted a prospective, double-blind, placebo-controlled trial in 155 outpatients with amyotrophic lateral sclerosis. The dose of riluzole was 100 mg per day. Randomization was stratified according to the site of disease onset (the bulbar region or the limbs). The primary end points were survival and rates of change in functional status. The main secondary end point was change in muscle strength. Analyses were undertaken after 12 months of treatment and at the end of the placebo-controlled period (median follow-up, 573 days). RESULTS: After 12 months, 45 of 78 patients (58 percent) in the placebo group were still alive, as compared with 57 of 77 patients (74 percent) in the riluzole group (P = 0.014). For patients with bulbar-onset disease, one-year survival rates were 35 percent (6 of 17) with placebo and 73 percent (11 of 15) with riluzole (P = 0.014), whereas for those with limb-onset disease one-year survival was 64 percent and 74 percent, respectively (P = 0.17). The survival advantage with riluzole was smaller (37 percent [29 of 78] with placebo vs. 49 percent [38 of 77] with riluzole) at the end of the placebo-controlled period, but it remained significant in the overall population (P = 0.046) as well as in the patients with bulbar-onset disease (18 percent [3 of 17] vs. 53 percent [8 of 15], P = 0.013). The deterioration of muscle strength was significantly slower in the riluzole group than in the placebo group (P = 0.028). Adverse reactions to riluzole included asthenia, spasticity, and mild elevations in aminotransferase levels. Twenty-seven patients in the riluzole group withdrew from the study, as compared with 17 in the placebo group. CONCLUSIONS: The antiglutamate agent riluzole appears to slow the progression of amyotrophic lateral sclerosis, and it may improve survival in patients with disease of bulbar onset.
8Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).PubMed
Robert G Miller, J D Mitchell, Dan H Moore
Cochrane Database Syst Rev. 2012 Mar 14;2012(3):CD001447. doi: 10.1002/14651858.CD001447.pub3.
BACKGROUND: Riluzole is approved for the treatment of amyotrophic lateral sclerosis in most countries. Questions persist about its clinical utility because of high cost and modest efficacy. OBJECTIVES: To examine the efficacy of riluzole in prolonging survival and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival, and to assess the effect of riluzole upon functional health. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (20 April 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 2), MEDLINE (1966 to April 2011), EMBASE (1980 to May 2011) and made enquiries of authors of trials, Aventis (manufacturer of riluzole) and other experts in the field. SELECTION CRITERIA: Types of studies: randomized controlled trials TYPES OF PARTICIPANTS: adults with a diagnosis of amyotrophic lateral sclerosis Types of interventions: treatment with riluzole or placebo Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality with riluzole 50 mg, 100 mg and 200 mg; neurologic function, muscle strength and adverse events. DATA COLLECTION AND ANALYSIS: One author performed data extraction and two other authors checked them. One author checked the data and entered them into the computer. The other authors verified the data entry. We obtained missing data from the trial authors whenever possible. MAIN RESULTS: The four trials examining tracheostomy-free survival included a total of 974 riluzole-treated patients and 503 placebo-treated patients. No new randomized controlled trials were found when we updated the searches for this update in 2011. The methodological quality was acceptable and three trials were easily comparable, although one trial (169 participants) included older patients in more advanced stages of amyotrophic lateral sclerosis and one (195 participants) had multiple primary endpoints. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (hazard ratio (HR) 0.80, 95% confidence internal (CI) 0.64 to 0.99, P= 0.042) and there was no evidence of heterogeneity (P = 0.33). When the third trial (which included older and more seriously affected patients) was added, there was evidence of heterogeneity (P < 0.0001) and the overall treatment effect was reduced but still significant (HR 0.84, 95% CI 0.698 to 0.997, P= 0.046). This represented a 9% gain in the probability of surviving one year (49% in the placebo and 58% in the riluzole group), and increased median survival from 11.8 to 14.8 months. There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. A three-fold increase in serum alanine transferase was more frequent in riluzole-treated patients than controls (mean difference 2.62, 95% CI 1.59 to 4.31). AUTHORS' CONCLUSIONS: Riluzole 100 mg daily is reasonably safe and probably prolongs median survival by about two to three months in patients with amyotrophic lateral sclerosis.
9Edaravone May Prevent Ferroptosis in ALS.PubMed
Snežana Spasić, Aleksandra Nikolić-Kokić, Srđan Miletić, et al.
Curr Drug Targets. 2020;21(8):776-780. doi: 10.2174/1389450121666200220123305.
Radicava™ (Edaravone) was approved the Food and Drug Administration (FDA) as a new treatment for amyotrophic lateral sclerosis (ALS). Edaravone is a synthetic antioxidant that specifically targets oxidative damage interacting with lipid radicals in the cell. In ALS disease the multiple cell types are involved in devastating loss of motor neurons. Mutations and biochemical changes in various cell types jointly contribute to motor neuron death, disease onset, and disease progression. The overall mechanism of neurodegeneration in ALS is still not completely understood. Dying motor neurons have been reported to exhibit features of apoptosis. However, non-apoptotic features of dying motor neurons have also been reported such as ferroptosis. The role of Edaravone in the prevention of ferroptosis in parallel with other therapeutic approaches to ALS therapy is discussed.
10Edaravone for the treatment of amyotrophic lateral sclerosis.PubMed
Hiide Yoshino
Expert Rev Neurother. 2019 Mar;19(3):185-193. doi: 10.1080/14737175.2019.1581610. Epub 2019 Feb 27.
Amyotrophic lateral sclerosis (ALS) is a progressive fatal disorder that affects all skeletal muscles, leading to death, mostly within 2-4 years from onset. To date, the anti-glutamatergic drug riluzole is the only drug that has been approved for the treatment of this disease; however, its efficacy is modest. Oxidative stress is considered to be involved in the pathology of ALS, and in this regard, the free radical scavenger edaravone, which was originally developed for the treatment of acute ischemic stroke, has also been developed for the treatment of ALS. Areas covered: This review describes the pharmacological properties of edaravone and the progress of clinical trials conducted to evaluate the efficacy of this drug in the treatment of ALS. Expert commentary: Edaravone is the first drug to show effective inhibition of the motor function deterioration experienced by ALS patients with early-stage probable and definite types. In order to effectively prolong the quality of motor function, edaravone treatment should be initiated as soon as the diagnosis has been confirmed; however, the respiratory function should be carefully monitored when a deterioration in breathing capacity is detected.
11Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial.PubMed
Lancet Neurol. 2017 Jul;16(7):505-512. doi: 10.1016/S1474-4422(17)30115-1. Epub 2017 May 15.
BACKGROUND: In a previous phase 3 study in patients with amyotrophic lateral sclerosis (ALS), edaravone did not show a significant difference in the Revised ALS Functional Rating Scale (ALSFRS-R) score compared with placebo. Post-hoc analysis of these data revealed that patients in an early stage with definite or probable diagnosis of ALS, defined by the revised El Escorial criteria, who met a select set of inclusion criteria showed a greater magnitude of effect than did the full study population. We aimed to substantiate this post-hoc result and assess safety and efficacy of edaravone in a phase 3 trial that focused on patients with early stage ALS who met the post-hoc analysis inclusion criteria. METHODS: In this phase 3, randomised, double-blind, parallel-group study, patients aged 20-75 years with ALS of grade 1 or 2 in the Japan ALS Severity Classification, scores of at least 2 points on all 12 items of ALSFRS-R, forced vital capacity of 80% or more, definite or probable ALS according to the revised El Escorial criteria, and disease duration of 2 years or less were recruited from 31 hospitals in Japan. Eligible patients also had a decrease of 1-4 points in the ALSFRS-R score during a 12-week observation period before randomisation. Patients meeting all criteria were then randomly assigned 1:1 to receive 60 mg intravenous edaravone or intravenous saline placebo for 6 cycles (4 weeks per cycle with 2 weeks on, 2 weeks off) for a total treatment duration of 24 weeks. In cycle 1, the study drug or placebo was administered once per day for 14 days within a 14 day period, followed by the drug-free period. In cycle 2 and thereafter, the study drug or placebo was administered for 10 days within a 14 day period, followed by a 2 week drug-free period. Participants and investigators, including those assessing outcomes, were masked to treatment allocation. The primary efficacy outcome was the change in ALSFRS-R score from the baseline to 24 weeks (or at discontinuation if this was after the third cycle) after randomisation. The primary outcome was assessed in all patients who had received at least one treatment infusion, had at least one assessment post-baseline, and reached the end of cycle 3. For patients with missing values at the end of cycle 6, data were imputed by the last observation carried forward (LOCF) method, provided the patients had completed at least cycle 3. Safety was assessed in all patients who had received at least one treatment infusion and had at least one assessment post-baseline. This trial is registered with ClinicalTrials.gov, NCT01492686. FINDINGS: Between Nov 28, 2011, and Sept 3, 2014, we screened 213 patients, and enrolled 192 as potential participants. Of these, 137 patients completed the observation period: 69 were randomly assigned to receive edaravone, and 68 were randomly assigned to receive placebo. 68 patients taking edaravone and 66 taking placebo were included in the primary efficacy analysis. For the primary outcome, the change in ALSFRS-R score was -5·01 (SE 0·64) in the edavarone group and -7·50 (0·66) in the placebo group. The least-squares mean difference between groups was 2·49 (SE 0·76, 95% CI 0·99-3·98; p=0·0013) in favour of edaravone. Treatment-emergent adverse events were reported in 58 (84%) patients receiving edaravone and 57 (84%) patients receiving placebo. 11 (16%) patients taking edaravone and 16 (24%) taking placebo had serious adverse events, and one (1%) patient receiving edaravone and four (6%) patients receiving placebo had adverse events (one dysphagia in edaravone group and one dyspnoea, two respiratory disorder, and one rash in the placebo group) that led to withdrawal. INTERPRETATION: Edaravone showed efficacy in a small subset of people with ALS who met criteria identified in post-hoc analysis of a previous phase 3 study, showing a significantly smaller decline of ALSFRS-R score compared with placebo. There is no indication that edaravone might be effective in a wider population of patients with ALS who do not meet the criteria. FUNDING: Mitsubishi Tanabe Pharma Corporation.
12Edaravone for patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.PubMed
Shi-Le Huang, Yin-Li Shen, Wen-Yan Peng, et al.
Acta Neurol Belg. 2024 Jun;124(3):895-904. doi: 10.1007/s13760-024-02476-2. Epub 2024 Feb 12.
BACKGROUND AND OBJECTIVE: The effectiveness and long-term efficacy of edaravone, a recommended treatment for amyotrophic lateral sclerosis (ALS), has not been examined in real-world settings. This study aims to evaluate the effectiveness and long-term efficacy of edaravone. METHODS: The OVID Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science databases were searched for articles published between January 1, 2000, and May 1, 2023. Two investigators independently screened the retrieved articles for randomized controlled trials (RCTs), cohort studies, or single-arm trials that evaluated the effect of edaravone on amyotrophic lateral sclerosis (ALS). The risk of bias was evaluated using the revised Cochrane Risk-of-Bias (RoB 2.0) tool for randomized controlled trials (RCTs) and the Risk-of-Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for observational studies. The primary outcome was the ALSFRS-R score assessed at month 6, with secondary outcomes including the ALSFRS-R scores evaluated at months 9, 12, and 18, forced vital capacity (FVC), and adverse events. The certainty of evidence was assessed using the GRADE approach. RESULTS: The analysis included 16 studies with a total of 4828 participants. Among these, four were randomized controlled trials (RCTs) and 12 were observational studies. Of the RCTs, four were rated as having a low risk of bias, while six of the observational studies were rated as having a low risk of bias. Edaravone was associated with slightly slower progression in the reduction of ALSFRS-R score at month 6 compared to placebo (mean difference 1.01, 95%CI -0.87 to 3.09, p = 0.293), as shown by evidence from RCTs. However, observational studies did not show any benefit of adding edaravone to routine practice (mean difference 1.85, 95%CI -2.05 to 5.75, p = 0.352). The change from baseline in ALSFRS-R score was -2.1, -4.04, -7.5, -6.82, and -7.9 at months 3, 6, 9, 12, and 18, respectively. The GRADE assessment indicated moderate certainty for evidence from RCTs, while evidence from observational studies had very low certainty. CONCLUSION: Due to the limited number of studies and confounding issues in observational studies, further examination of the added benefits of edaravone to routine practice is necessary through RCTs, particularly regarding its long-term efficacy.
13Critical issues in the use of edaravone for the treatment of amyotrophic lateral sclerosis.PubMed
Hung Youl Seok
Neurol Sci. 2025 Aug;46(8):3427-3430. doi: 10.1007/s10072-025-08154-2. Epub 2025 Apr 8.
Edaravone, along with riluzole, is a key treatment for amyotrophic lateral sclerosis (ALS), with evidence supporting its efficacy in slowing disease progression, particularly in patients with early-stage ALS. Despite its approval and increasing clinical use, several critical questions about its use remain unanswered: Can edaravone be effective as monotherapy? Is it beneficial for patients who fall outside the inclusion criteria of pivotal trials? What is the optimal duration of treatment as ALS progresses? In addition, does edaravone provide clinical benefit to patients with familial ALS? Answering these questions is essential to optimize the use of edaravone in clinical practice and to further our understanding of its role in the treatment of ALS. This review synthesizes the current evidence to address these questions and identifies areas that require further investigation.
14[Amyotrophic lateral sclerosis (ALS) - diagnosis, course of disease and treatment options].PubMed
Thomas Meyer
Dtsch Med Wochenschr. 2021 Dec;146(24-25):1613-1618. doi: 10.1055/a-1562-7882. Epub 2021 Dec 8.
Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disorder which is characterized by progressive motor symptoms, such as muscle weakness, muscle atrophy and spasticity. In Germany, 6000-8000 people are affected by ALS. Between 1200 and 1600 newly diagnosed patients are expected each year. Protein deposits in the cytoplasm of motor neurons are a molecular feature of ALS. The most common protein aggregates result from excessive deposition of TDP-43. Familial ALS is present in 5 to 10 % of all ALS patients. Common causal genes include C9orf72, SOD1, FUS, and TARDBP. Genetic factors may be involved even without a family history of ALS and may be underestimated. The disease course and progression are highly variable. Symptom severity and rate of progression are determined by the ALS Functional Scale (ALSFRS-R). Beyond clinical symptoms and the patient's perception of disease burden, measurement of slow vital capacity (SVC), peak cough flow (PCF), and body mass index (BMI) are used to underscore the indications for ventilatory and nutritional interventions, as well as palliative care. The validity of the biomarker neurofilament light chain (NF-L) for estimating prognosis is currently being investigated. ALS is not curable - however, various individual treatment options have to be considered for improving survival, symptom control and social participation. The care in specialized ALS centers is recommended to ensure optimal treatment regarding symptomatic medication, assistive devices, nutrition support and ventilation therapy. Optimal care is achieved by interdisciplinary collaboration of general practitioners, specialized physicians, neurologists and ALS experts being integrated in multiprofessional care networks.
15Pathogenesis and presentation of ALS: examining reasons for delayed diagnosis and identifying opportunities for improvement.PubMed
Karen Lynch
Am J Manag Care. 2023 Jun;29(7 Suppl):S104-S111. doi: 10.37765/ajmc.2023.89390.
Amyotrophic lateral sclerosis (ALS), or Lou Gehrig disease, is a progressive, always-fatal neuromuscular disease characterized by motor neuron degeneration in the brain and spinal cord. As upper and lower motor neurons fail, inability to transmit messages to the muscles causes muscle stiffness, atrophy, and wasting. The incidence of this incurable disease is increasing in the United States, and its prognosis is grim. On average, patients survive about 3 to 5 years from symptom onset. Until recently, few risk factors were known, but some are newly emerging. About 10% of cases are related to genetic variants. Patients who develop ALS often experience diagnostic delays (10-16 months on average), and its heterogeneity contributes to that delay. Diagnosis is based primarily on clinical signs and symptoms and exclusion of other causes of motor neuron dysfunction. Reliable, accessible biomarkers are needed to aid early ALS diagnosis, differentiate from ALS-mimicking diseases, predict survival, and monitor disease progression and treatment response. Misdiagnosing ALS can have devastating consequences, including unnecessary emotional burden, delayed and/or inappropriate treatment, and undue financial burden. The grim prognosis and sure progression to death creates considerable burden and reduces quality of life for patients and caregivers.
16Primary lateral sclerosis: a distinct entity or part of the ALS spectrum?PubMed
Eoin Finegan, Rangariroyashe H Chipika, Stacey Li Hi Shing, et al.
Amyotroph Lateral Scler Frontotemporal Degener. 2019 May;20(3-4):133-145. doi: 10.1080/21678421.2018.1550518. Epub 2019 Jan 18.
Primary lateral sclerosis (PLS) has been traditionally viewed as a distinct upper motor neuron condition (UMN) but is increasingly regarded as a sub-phenotype within the amyotrophic lateral sclerosis (ALS) spectrum. Despite established diagnostic criteria, formal diagnosis can be challenging and the protracted diagnostic journey and uncertainty about longer-term prognosis cause considerable distress to patients and caregivers. PLS patients are invariably excluded from ALS clinical trials, while PLS pharmacological trials are lacking. There remains an unmet need for diagnostic biomarkers for upper motor neuron predominant conditions and prognostic indicators regarding prognosis, survival, and risk of conversion to ALS. Validated biomarkers will not only have implications for individualized patient care but also serve as outcome measures in pharmaceutical trials. Given the paucity of post-mortem studies in PLS, novel pathological insights are generally inferred from state-of-the-art imaging studies. Computational neuroimaging has already contributed significantly to the characterization of PLS-associated pathology and has underscored the role of neuro-inflammation, the presence of extra-motor changes, and confirmed pathological patterns similar to ALS. This systematic review assesses the current state of PLS research across clinical, neuroimaging and neuropathological domains from a combined clinical and academic perspective. We discuss patterns of pathological overlap with other ALS phenotypes, examine if the biological processes of PLS warrant therapeutic strategies distinct from ALS, and evaluate the evidence that classes PLS as a distinct clinico-pathological entity.
17Relational, Ethical, and Care Challenges in ALS: A Systematic Review and Qualitative Metasynthesis of Nurses' Perspectives.PubMed
Giovanna Artioli, Luca Guardamagna, Nicole Succi, et al.
Brain Sci. 2025 Jun 3;15(6):600. doi: 10.3390/brainsci15060600.
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to severe functional decline and death, imposing significant physical, emotional, and ethical burdens on patients and healthcare providers. With no curative treatment, ALS care depends on the early and sustained integration of palliative care to address complex and evolving needs. Nurses play a pivotal role in this process, yet their lived experiences remain underexplored. This study aimed to synthesize qualitative evidence on nurses' experiences in ALS care, with a focus on emotional, ethical, and palliative dimensions. METHODS: A meta-synthesis of qualitative studies was conducted using Sandelowski and Barroso's four-step method. A systematic search across five databases identified eight studies exploring nurses' experiences with ALS care. Thematic synthesis was applied to extract overarching patterns. RESULTS: Three core themes emerged: (1) : and -emphasizing communication barriers and the value of relational trust; (2) : , , and -highlighting the emotional demands of care, the need for timely palliative integration, and the professional meaning derived from ALS care; (3) : and -exploring dilemmas around life-sustaining treatments, patient autonomy, and end-of-life decisions. CONCLUSION: Nurses in ALS care face complex emotional and ethical challenges that call for strong institutional support and palliative training. Enhancing palliative care integration from diagnosis, alongside targeted education and psychological support, is crucial to improving care quality and sustaining the well-being of both patients and nurses.
18Palliative Care in Amyotrophic Lateral Sclerosis.PubMed
Sebastiano Mercadante, Lou'i Al-Husinat
J Pain Symptom Manage. 2023 Oct;66(4):e485-e499. doi: 10.1016/j.jpainsymman.2023.06.029. Epub 2023 Jun 26.
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease of the motor neurons. Given the evolutive characteristics of this disease, palliative care principles should be a foundation of ALS care. A multidisciplinary medical intervention is of paramount importance in the different phases of disease. The involvement of the palliative care team improves quality of life and symptoms, and prognosis. Early initiation is of paramount importance to ensuring patient-centered care, when the patient has still the capability to communicate effectively and participate in his medical care. Advance care planning supports patients and family members in understanding and sharing their preferences according to their personal values and life goals regarding future medical treatment. The principal problems which require intensive supportive care include cognitive disturbances, psychological distress, pain, sialorrhrea, nutrition, and ventilatory support. Communication skills of health-care professionals are mandatory to manage the inevitability of death. Palliative sedation has peculiar aspects in this population, particularly with the decision of withdrawing ventilatory support.
19Ultra-high dose methylcobalamin and other emerging therapies for amyotrophic lateral sclerosis.PubMed
Ryuji Kaji, Yuishin Izumi, Ryosuke Oki
Curr Opin Neurol. 2024 Oct 1;37(5):593-602. doi: 10.1097/WCO.0000000000001311. Epub 2024 Jul 31.
PURPOSE OF REVIEW: Recent development in understanding the pathophysiology of amyotrophic lateral sclerosis (ALS) has led to increasing number of promising test drugs in the pipeline along with the existing ones. We will review these agents focusing on ultra-high dose methylcobalamin, which is pending approval in Japan. Clinical trial design best suited for ALS will also be discussed. RECENT FINDINGS: The most recent phase 3 trial (JETALS) of ultra-high dose methylcobalamin demonstrated significant slowing of ALSFRSR changes (0.5/month), with marked reduction of serum homocysteine levels in the initial double-blind period. The post hoc analysis of the previous phase 2/3 study (E761 trial; Eisai) showed that it prolonged survival of ALS patients, if started within 1 year of onset, but the previous studies suggested its efficacy even in later stages, depending upon the rate of progression. Phase 3 trial of AMX0035 or Relyvrio on the other hand showed negative results despite the promising phase 2 data. The latter did not adjust the disease progression rate before entry. SUMMARY: Ultra-high dose methylcobalamin is not a vitamin supplement but a novel disease-modifying therapy for ALS, and it emphasizes homocysteine as a key factor in the disease process. Clinical trial design must include entering patients early and with similar rates of progression using pretrial observation periods for meaningful results, since ALS is a chronologically heterogenous condition with similar phenotypes.
20Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.PubMed
Ryosuke Oki, Yuishin Izumi, Koji Fujita, et al.
JAMA Neurol. 2022 Jun 1;79(6):575-583. doi: 10.1001/jamaneurol.2022.0901.
IMPORTANCE: The effectiveness of currently approved drugs for amyotrophic lateral sclerosis (ALS) is restricted; there is a need to develop further treatments. Initial studies have shown ultrahigh-dose methylcobalamin to be a promising agent. OBJECTIVE: To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS enrolled within 1 year of onset. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, placebo-controlled, double-blind, randomized phase 3 clinical trial with a 12-week observation and 16-week randomized period, conducted from October 17, 2017, to September 30, 2019. Patients were recruited from 25 neurology centers in Japan; those with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1- or 2-point decrease in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score, a percent forced vital capacity greater than 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulatory. The target participant number was 64 in both the methylcobalamin and placebo groups. Patients were randomly assigned through an electronic web-response system to methylcobalamin or placebo. INTERVENTIONS: Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set. RESULTS: A total of 130 patients (mean [SD] age, 61.0 [11.7] years; 74 men [56.9%]) were randomly assigned to methylcobalamin or placebo (65 each). A total of 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Of these, 124 patients proceeded to the open-label extended period. The least square means difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (-2.66 vs -4.63; 95% CI, 0.44-3.50; P = .01). The incidence of adverse events was similar between the 2 groups. CONCLUSIONS AND RELEVANCE: Results of this randomized clinical trial showed that ultrahigh-dose methylcobalamin was efficacious in slowing functional decline in patients with early-stage ALS and with moderate progression rate and was safe to use during the 16-week treatment period. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03548311.
21[Clinical trials of ultra-high-dose methylcobalamin in ALS].PubMed
Yuishin Izumi, Ryuji Kaji
Brain Nerve. 2007 Oct;59(10):1141-7.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting both upper and lower motor neurons. Weakness may begin in the legs, hands, proximal arms, or pharynx. The course is relentless and progressive without remissions, relapses, or even stable plateaus. There is no effective drug therapy for ALS, although riluzole has been shown to prolong life in sufferers, without tracheostomy. A vitamin B12 analog, methylcobalamin, has a protective effect on cultured cortical neurons against glutamate-induced cytotoxicity. We have shown the ultra-high-dose methylcobalamin (25 mg/day i.m.) slows down the progressive reduction of the CMAP (compound muscle action potential) amplitudes in ALS in the short term (4 weeks). The latencies of SSR (sympathetic skin response) were shorter after treatment (50 mg/day i.v., 2 weeks). In the long-term effect of methylcobalamin (50 mg/day i.m., twice a week), the survival time (or the period to become respirator-bound) was significantly longer in the treated group than in the untreated. Larger-scale randomized double blind trial was started in Japan in order to evaluate the long-term efficacy and the safety of ultra-high-dose methylcobalamin for sporadic or familial cases of ALS.
22Neuroprotective effect of ultra-high dose methylcobalamin in wobbler mouse model of amyotrophic lateral sclerosis.PubMed
Ken Ikeda, Yasuo Iwasaki, Ryuji Kaji
J Neurol Sci. 2015 Jul 15;354(1-2):70-4. doi: 10.1016/j.jns.2015.04.052. Epub 2015 May 8.
BACKGROUND: High-dose of methylcobalamin promotes nerve regeneration in rats with acrylamide neuropathy. A double-blind controlled trial suggested that high-dose methylcobalamin could increase compound muscle action potentials in patients with amyotrophic lateral sclerosis (ALS). A large-scale extended period human trial is now on-going in ALS (Clinicaltrial.govNCT00444613). We attempted to study whether high-dose methylcobalamin can improve symptoms or retard progression of motor dysfunction in the wobbler mouse model of ALS. METHODS: After initial diagnosis of the disease at the postnatal age of 3-4 weeks, wobbler mice received methylcobalamin (3 or 30 mg/kg, n=10/group) or vehicle (n=10), daily for 4 weeks by intraperitoneal administration in a blinded fashion. We compared clinical symptoms and pathological changes among all groups. Vitamin B12 concentrations were measured in the serum, the skeletal muscle and the spinal cord of three groups (n=5/group). RESULTS: In comparison with vehicle, mice treated with ultra-high dose (30 mg/kg) of methylcobalamin significantly inhibited muscle weakness and contracture in the forelimb, and increased the weight of the bicep muscles and the number of musculocutaneous nerves. Methylcobalamin-treated mice significantly elevated vitamin B12 concentrations of the serum, the bicep muscle and the spinal cord compared to vehicle. CONCLUSION: Our results suggest that treatment with methylcobalamin could delay progression of motor symptoms and neuropathological changes in wobbler mouse motor neuron disease if very high doses are used.
23Ultra-high-dose methylcobalamin in amyotrophic lateral sclerosis: a long-term phase II/III randomised controlled study.PubMed
Ryuji Kaji, Takashi Imai, Yasuo Iwasaki, et al.
J Neurol Neurosurg Psychiatry. 2019 Apr;90(4):451-457. doi: 10.1136/jnnp-2018-319294. Epub 2019 Jan 13.
OBJECTIVE: To evaluate the efficacy and safety of intramuscular ultra-high-dose methylcobalamin in patients with amyotrophic lateral sclerosis (ALS). METHODS: 373 patients with ALS (El Escorial definite or probable; laboratory-supported probable; duration ≤36 months) were randomly assigned to placebo, 25 mg or 50 mg of methylcobalamin groups. The primary endpoints were the time interval to primary events (death or full ventilation support) and changes in the Revised ALS Functional Rating Scale (ALSFRS-R) score from baseline to week 182. Efficacy was also evaluated using post-hoc analyses in patients diagnosed early (entered ≤12 months after symptom onset). RESULTS: No significant differences were detected in either primary endpoint (minimal p value=0.087). However, post-hoc analyses of methylcobalamin-treated patients diagnosed and entered early (≤12 months' duration) showed longer time intervals to the primary event (p<0.025) and less decreases in the ALSFRS-R score (p<0.025) than the placebo group. The incidence of treatment-related adverse events was similar and low in all groups. CONCLUSION: Although ultra-high-dose methylcobalamin did not show significant efficacy in the whole cohort, this treatment may prolong survival and retard symptomatic progression without major side effects if started early. TRIAL REGISTRATION NUMBER: NCT00444613.
24[JETALS: The Japanese Early-stage Trial of high dose methylcobalamin for ALS].PubMed
Yuishin Izumi, Ryosuke Oki, Satoshi Kuwabara, et al.
Brain Nerve. 2019 Nov;71(11):1261-1269. doi: 10.11477/mf.1416201436.
High-dose methylcobalamin was found to be a therapeutic candidate for amyotrophic lateral sclerosis (ALS) through clinical experience. Our previous study (E0302-J081-761) has suggested that high-dose methylcobalamin (E0302) prolonged the overall survival and suppressed progression in ALS patients with a disease duration less than 12 months in, exploratory analyses. Therefore, we plan to conduct an investigator-initiated trial "The Japan Early-stage Trial of high dose methylcobalamin for ALS (JETALS)" to evaluate the efficacy and safety of E0302 for ALS patients within 12 months from onset. JETALS is a prospective, multicenter, placebo-controlled, double-blind, randomized Phase III study, conducted at 25 tertiary neurology centers, and is funded by the Japan Agency for Medical Research and Development. A total of 128 patients were randomized at a 1:1 ratio to receive intramuscular injection with E0302 50 mg or placebo, twice a week for 16 weeks. The primary endpoint is changes in the ALS Functional Rating Scale (ALSFRS-R) total score at 16 weeks. The patient enrollment period is from November 2017 to September 2019, and the follow-up is scheduled to end in March 2020. If the results are positive, we intend to apply for E0302 approval for methylcobalamin as a new drug for treating ALS.
25The Japanese Early-Stage Trial of High-Dose Methylcobalamin for Amyotrophic Lateral Sclerosis (JETALS): Protocol for a Randomized Controlled Trial.PubMed
Ryosuke Oki, Yuishin Izumi, Hiroyuki Nodera, et al.
JMIR Res Protoc. 2018 Dec 21;7(12):e12046. doi: 10.2196/12046.
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. Currently, only riluzole and edaravone are approved as drugs to treat ALS and new agents with larger effect sizes are warranted. Exploratory analyses in our previous study (study ID #E0302-J081-761) have suggested that high-dose methylcobalamin (E0302) prolonged the overall survival of ALS patients and suppressed ALS progression in patients with a disease duration of less than 12 months. OBJECTIVE: This clinical trial aims to evaluate the efficacy and safety of E0302 for treatment of ALS patients within one year of onset. METHODS: The Japanese early-stage trial of high-dose methylcobalamin for ALS (JETALS) is a prospective, multicenter, placebo-controlled, double-blind, randomized phase III study conducted at 24 tertiary neurology centers and is funded by the Japan Agency for Medical Research and Development. A total of 128 ALS patients within one year of onset were randomized at a 1:1 ratio to receive intramuscular injection with E0302 50 mg or placebo twice a week for 16 weeks. The primary endpoint is changes in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score at 16 weeks. If patients wish to receive E0302 50 mg after the double-blind administration period, E0302 will be provided to them until March 2020 during the continuous administration period. RESULTS: This study began in October 2017 and is being conducted at 24 participating institutions in Japan. The study is in progress and the patient enrollment period is scheduled to end in August 2019, with follow-up scheduled to end in March 2020. CONCLUSIONS: This study is being performed to revalidate the efficacy and safety of E0302 in patients with early-stage ALS in the first year of symptom onset. If positive results are obtained, the aim is to apply for E0302 approval as a new drug for the treatment of ALS. TRIAL REGISTRATION: ClinicalTrials.gov NCT03548311; https://clinicaltrials.gov/ct2/show/NCT03548311 (Archived by WebCite at http://www.webcitation.org/74Fw3rDzb). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/12046.
26Profiling tofersen as a treatment of superoxide dismutase 1 amyotrophic lateral sclerosis.PubMed
Miguel Oliveira Santos, Mamede de Carvalho
Expert Rev Neurother. 2024 Jun;24(6):549-553. doi: 10.1080/14737175.2024.2355983. Epub 2024 May 17.
INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neuron disorder with a fatal outcome 3-5 years after disease onset due to respiratory complications. Superoxide dismutase 1 (SOD1) mutations are found in about 2% of all patients. Tofersen is a novel oligonucleotide antisense drug specifically developed to treat SOD1-ALS patients. AREAS COVERED: Our review covers and discusses tofersen pharmacological properties and its phase I/II and III clinical trials results. Other available drugs and their limitations are also addressed. EXPERT OPINION: VALOR study failed to meet the primary endpoint (change in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale score from baseline to week 28, tofersen arm vs. placebo), but a significant reduction in plasma neurofilament light chain (NfL) levels was observed in tofersen arm (60% vs. 20%). PrefALS study has proposed plasma NfL has a potential biomarker for presymptomatic treatment, since it increases 6-12 months before phenoconversion. There is probably a delay between plasma NfL reduction and the clinical benefit. ATLAS study will allow more insights regarding tofersen clinical efficacy in disease progression rate, survival, and even disease onset delay in presymptomatic SOD1 carriers.
27TofersenPubMed
John L. Cerillo, Mayur Parmar
Tofersen, a novel antisense oligonucleotide (ASO) drug, received accelerated approval from the U.S. Food and Drug Administration (FDA) in April 2023 for the treatment of amyotrophic lateral sclerosis (ALS). ALS is a progressive, fatal neurodegenerative disorder affecting motor neurons in the brain and spinal cord, leading to muscle weakness, paralysis, and eventual death. Tofersen is specifically indicated for ALS patients with a superoxide dismutase 1 (SOD1) gene mutation. The mutant SOD1 protein resulting from this gene mutation gains a toxic function and significantly increases SOD1 messenger RNA (mRNA) levels and protein in the cerebrospinal fluid (CSF). This activity provides comprehensive information about Tofersen's indications, contraindications, mechanism of action, adverse event profile, monitoring, and relevant interactions relevant to patients and healthcare team members involved in treating patients with ALS and related conditions.
28Recent Progress of Antisense Oligonucleotide Therapy for -Mutated Amyotrophic Lateral Sclerosis: Focus on Tofersen.PubMed
Hidenori Moriyama, Toshifumi Yokota
Genes (Basel). 2024 Oct 20;15(10):1342. doi: 10.3390/genes15101342.
Amyotrophic lateral sclerosis (ALS) is a refractory neurodegenerative disease characterized by the degeneration and loss of motor neurons, typically resulting in death within five years of onset. There have been few effective treatments, making the development of robust therapies an urgent challenge. Genetic mutations have been identified as contributors to ALS, with mutations in (), which neutralizes the harmful reactive oxygen species superoxide, accounting for approximately 2% of all ALS cases. To counteract the toxic gain of function caused by mutations, therapeutic strategies aimed at suppressing gene expression have shown promise. Antisense oligonucleotide (ASO) is an artificially synthesized, short, single-stranded DNA/RNA molecule that binds to target RNA to alter gene expression, representing a next-generation therapeutic approach. In 2023, tofersen became the first ASO drug approved by the FDA for ALS. Administered intrathecally, tofersen specifically binds to mRNA, inhibiting the production of toxic SOD1 protein, thereby improving biomarkers of ALS. The long-term efficacy and safety of tofersen require further validation, and the development of more optimized treatment protocols is essential. A series of studies and therapeutic developments related to mutations have advanced the understanding of ALS pathophysiology and significantly contributed to treatment strategies for central nervous system disorders. This review focuses on an overview of mutations and the development process of tofersen, aiming to deepen the understanding of advancements in ALS research and discuss future challenges and directions for ASO therapy.
29Trial of Antisense Oligonucleotide Tofersen for ALS.PubMed
Timothy M Miller, Merit E Cudkowicz, Angela Genge, et al.
N Engl J Med. 2022 Sep 22;387(12):1099-1110. doi: 10.1056/NEJMoa2204705.
BACKGROUND: The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in ( ALS). METHODS: In this phase 3 trial, we randomly assigned adults with ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. The primary end point was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) among participants predicted to have faster-progressing disease. Secondary end points included changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its open-label extension at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort). RESULTS: A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients. CONCLUSIONS: In persons with ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events. The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.).
30Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for ALS.PubMed
Timothy Miller, Merit Cudkowicz, Pamela J Shaw, et al.
N Engl J Med. 2020 Jul 9;383(2):109-119. doi: 10.1056/NEJMoa2003715.
BACKGROUND: Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to mutations. METHODS: We conducted a phase 1-2 ascending-dose trial evaluating tofersen in adults with ALS due to mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured. RESULTS: A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture-related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], -18 to 27) for the 20-mg dose, -25 percentage points (95% CI, -40 to -5) for the 40-mg dose, -19 percentage points (95% CI, -35 to 2) for the 60-mg dose, and -33 percentage points (95% CI, -47 to -16) for the 100-mg dose. CONCLUSIONS: In adults with ALS due to mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture-related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT number, 2015-004098-33.).
31Tofersen for SOD1 amyotrophic lateral sclerosis: a systematic review and meta-analysis.PubMed
Abdullah Ashraf Hamad, Ibraheem M Alkhawaldeh, Abdulqadir J Nashwan, et al.
Neurol Sci. 2025 May;46(5):1977-1985. doi: 10.1007/s10072-025-07994-2. Epub 2025 Jan 17.
OBJECTIVE: Tofersen, an antisense oligonucleotide, has recently received FDA and EMA approval for treating amyotrophic lateral sclerosis (ALS) in adults with SOD1 gene mutations. This systematic review and meta-analysis synthesized evidence on tofersen's safety and efficacy in patients with SOD1-related ALS. METHODS: A comprehensive search of three databases was conducted from inception through October 2024. Eligible studies included clinical trials, observational studies, and case studies. Meta-analyses were conducted using a random-effects model in RevMan. RESULTS: Twelve studies involving 195 patients treated with tofersen met the inclusion criteria, comprising two randomized controlled trials (RCTs), five cohort studies, one case series, and four case reports. Tofersen demonstrated promising effects, notably reducing SOD1 levels in cerebrospinal fluid and neurofilament light chain (NfL) in plasma, a biomarker strongly correlated with ALS progression and survival. Meta-analysis of RCTs showed a significantly lower rate of decline in ALS Functional Rating Scale-Revised (ALSFRS-R) scores from baseline in the tofersen group compared to placebo (SMD = 0.44, 95% CI [0.05 to 0.83], P = 0.03) and a significant reduction in the decline of predicted Slow Vital Capacity (P = 0.005). In a pre-post meta-analysis of five studies, a significant decrease in ALS progression rate (ALSFRS-R decline rate) was observed (MD = -0.28, 95% CI [-0.40 to -0.15], P < 0.0001). Reported adverse events were consistent with ALS progression or procedural effects. CONCLUSION: Current evidence suggests that tofersen effectively reduces SOD1 and NfL levels and slow disease progression in SOD1 ALS, showing promise as a targeted therapeutic option.
32Tofersen for SOD1 ALS.PubMed
William H Everett, Robert C Bucelli
Neurodegener Dis Manag. 2024;14(5):149-160. doi: 10.1080/17582024.2024.2402216. Epub 2024 Sep 27.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition affecting the motor system. The heterogenous nature of ALS complicates trial design. Genetic forms of ALS present an opportunity to intervene in a less heterogeneous population. ALS associated with gain of function mutations in make 'knock-down' strategies an attractive therapeutic approach. Tofersen, an antisense oligonucleotide that reduces expression of SOD1 via RNAase mediated degradation of mRNA, has shown robust effects on ALS biomarkers. While a Phase III trial of tofersen failed to meet its primary end point, open label extension data suggests that tofersen slows progression of SOD1 ALS.
33Tofersen: A Review in Amyotrophic Lateral Sclerosis Associated with SOD1 Mutations.PubMed
Aisling McGuigan, Hannah A Blair
CNS Drugs. 2025 Sep;39(9):903-912. doi: 10.1007/s40263-025-01204-5. Epub 2025 Jul 10.
Tofersen (QALSODY) is the first drug approved for the treatment of amyotrophic lateral sclerosis (ALS) associated with superoxide dismutase 1 (SOD1) mutations. Tofersen is an antisense oligonucleotide that induces SOD1 mRNA degradation. In the 28-week, placebo-controlled, multinational, phase III VALOR trial, intrathecally administered tofersen reduced plasma concentrations of neurofilament proteins (biomarker for neuro-axonal injury) and total SOD1 protein in cerebrospinal fluid in patients with SOD1 mutation-associated ALS. These reductions were sustained in a long-term, open-label extension study. The decline in functional outcomes was not significantly reduced with tofersen treatment compared with placebo in the 28-week phase III trial, although in the longer-term open-label study, early tofersen initiation was associated with slowed functional decline versus delayed tofersen initiation. Tofersen had an acceptable tolerability profile in clinical trials with a favourable benefit-to-risk balance. In summary, tofersen is a new disease-modifying therapy for patients with ALS attributed to an SOD1 mutation, offering reductions in levels of a biomarker associated with neurodegeneration and disease progression, with an acceptable tolerability profile.
34Concurrent nanotherapeutics and regulatory updates for the management of amyotrophic lateral sclerosis: a focused review for orphan drug (Tofersen).PubMed
Abhiram Kumar, Shivang Shukla, Anjali Rai, et al.
Orphanet J Rare Dis. 2025 Nov 21;20(1):598. doi: 10.1186/s13023-025-04042-2.
BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder affecting nerve cells in the brain and spinal cord. With a global incidence of 1.9 to 6 per 100,000 people, ALS is slightly more common in men and prevalent in individuals over 60. However, this review provides a concise update on the regulatory landscape and therapeutic advancements in managing ALS, focusing on the recent approval of Tofersen, the first gene therapy specifically targeting SOD1 mutation-related ALS. RESULTS: It highlights Tofersen unique role as an orphan drug approved by the US FDA, emphasizing its mechanism of action, gene silencing and its impact on reducing neurodegeneration. Additionally, the review synthesizes data from ongoing clinical trials, pharmacovigilance reports, and case studies to comprehensively understand Tofersen's safety, efficacy and market exclusivity. Beyond this, it explores the emerging potential of nanotherapeutic approaches to ALS treatment, identifying critical research gaps and future directions. CONCLUSION: Integrating regulatory updates, clinical evidence, and innovative therapeutic strategies, the review uniquely contributes to the ALS literature by bridging current treatment realities with potential future therapies, aiming to inform researchers, clinicians, and policymakers on optimizing ALS management.
35The sense of antisense therapies in ALS.PubMed
Sien H Van Daele, Pegah Masrori, Philip Van Damme, et al.
Trends Mol Med. 2024 Mar;30(3):252-262. doi: 10.1016/j.molmed.2023.12.003. Epub 2024 Jan 11.
Treatment of patients with amyotrophic lateral sclerosis (ALS) has entered a new era now that encouraging results about antisense oligonucleotides (ASOs) are becoming available and a first ASO therapy for ALS has been approved by the FDA. Moreover, there is hope not only that ALS can be stopped but also that symptoms can be reversed. Until now, degrading ASOs seemed to be successful mostly for rarer forms of familial ALS. However, the first attempts to correct mis-splicing events in sporadic ALS are underway, as well as a clinical trial examining interference with a genetic modifier. In this review, we discuss the current status of using ASOs in ALS and the possibilities and pitfalls of this therapeutic strategy.
36[Current Landscape of Tofersen in SOD-1-associated Amyotrophic Lateral Sclerosis].PubMed
Taro Ishiguro, Tetsuya Nagata, Takanori Yokota
Brain Nerve. 2024 Nov;76(11):1233-1239. doi: 10.11477/mf.1416202765.
Since the identification, in 1993, of the causative gene for familial amyotrophic lateral sclerosis (ALS), which is associated with SOD1 mutations, research has focused on the pathogenesis and therapeutics of ALS for more than 30 years. Tofersen, a highly anticipated gene-specific therapy that has been aligned with the disease-specific pathology, has been approved for marketing by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) However, as significant data on tofersen's safety and efficacy are required, the evaluation of this treatment is ongoing. This paper introduces the current clinical and commercial status of Tofersen, along with expectations for its approval in Japan.
37Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study.PubMed
Michael Benatar, Joanne Wuu, Peter M Andersen, et al.
Neurotherapeutics. 2022 Jul;19(4):1248-1258. doi: 10.1007/s13311-022-01237-4. Epub 2022 May 18.
Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying causes of ALS has made it difficult to target upstream biological mechanisms of disease, and therapeutic interventions are usually administered relatively late in the course of disease. Genetic forms of ALS offer a unique opportunity for therapeutic development, as genetic associations may reveal potential insights into disease etiology. Genetic ALS may also be amenable to investigating earlier intervention given the possibility of identifying clinically presymptomatic, at-risk individuals with causative genetic variants. There is increasing evidence for a presymptomatic phase of ALS, with biomarker data from the Pre-Symptomatic Familial ALS (Pre-fALS) study showing that an elevation in blood neurofilament light chain (NfL) precedes phenoconversion to clinically manifest disease. Tofersen is an investigational antisense oligonucleotide designed to reduce synthesis of superoxide dismutase 1 (SOD1) protein through degradation of SOD1 mRNA. Informed by Pre-fALS and the tofersen clinical development program, the ATLAS study (NCT04856982) is designed to evaluate the impact of initiating tofersen in presymptomatic carriers of SOD1 variants associated with high or complete penetrance and rapid disease progression who also have biomarker evidence of disease activity (elevated plasma NfL). The ATLAS study will investigate whether tofersen can delay the emergence of clinically manifest ALS. To our knowledge, ATLAS is the first interventional trial in presymptomatic ALS and has the potential to yield important insights into the design and conduct of presymptomatic trials, identification, and monitoring of at-risk individuals, and future treatment paradigms in ALS.
38Serious Neurologic Adverse Events in Tofersen Clinical Trials for Amyotrophic Lateral Sclerosis.PubMed
Alexandra Lovett, Sowmya Chary, Suma Babu, et al.
Muscle Nerve. 2025 Jun;71(6):1006-1015. doi: 10.1002/mus.28372. Epub 2025 Feb 27.
INTRODUCTION/AIMS: Tofersen is approved for the treatment of amyotrophic lateral sclerosis (ALS) due to superoxide dismutase 1 mutations (SOD1-ALS). Here we report serious neurologic adverse events (AEs) that occurred in the tofersen clinical trials in people with SOD1-ALS. METHODS: Serious neurologic AEs of myelitis, radiculitis, aseptic meningitis, and papilledema reported in the tofersen clinical trials are described. Serious AEs were defined according to International Conference for Harmonization guidelines, and neurologic AEs in clinical trials were diagnosed by investigators based on symptoms, clinical examination findings, and diagnostic workup. RESULTS: Ten participants (approximately 7% of tofersen 100-mg-treated trial participants) experienced a total of 12 serious neurologic AEs-4 of myelitis, 2 of radiculitis, 2 of aseptic meningitis, and 4 of intracranial hypertension (ICH) and/or papilledema. All events but one resolved either spontaneously, with dosing interruption/modification, or with concomitant therapies. One event was ongoing but improved as of December 2022. While 3 events led to tofersen treatment discontinuation, all other participants were able to remain on treatment. No event was life-threatening or fatal. DISCUSSION: Some antisense oligonucleotides (ASOs) have been described as having pro-inflammatory properties. Aseptic meningitis has been reported with nusinersen; however, myelitis, radiculitis, increased intracranial pressure, and papilledema have not been reported with ASO treatment. These neurologic AEs should be considered when assessing the overall benefit/risk of tofersen treatment for SOD1-ALS. Safety data from the open-label extension and expanded access program will continue to characterize these events and further inform the safety profile of tofersen in SOD1-ALS.
39Gene therapy for ALS: A review.PubMed
Defne A Amado, Beverly L Davidson
Mol Ther. 2021 Dec 1;29(12):3345-3358. doi: 10.1016/j.ymthe.2021.04.008. Epub 2021 Apr 9.
Amyotrophic lateral sclerosis (ALS) has historically posed unique challenges for gene-therapy-based approaches, due to a paucity of therapeutic targets as well as the difficulty of accessing both the brain and spinal cord. Recent advances in our understanding of disease mechanism and ALS genetics, however, have combined with tremendous strides in CNS targeting, gene delivery, and gene editing and knockdown techniques to open new horizons of therapeutic possibility. Gene therapy clinical trials are currently underway for ALS patients with SOD1 mutations, C9orf72 hexanucleotide repeat expansions, ATXN2 trinucleotide expansions, and FUS mutations, as well as sporadic disease without known genetic cause. In this review, we provide an in-depth exploration of the state of ALS-directed gene therapy, including antisense oligonucleotides, RNA interference, CRISPR, adeno-associated virus (AAV)-mediated trophic support, and antibody-based methods. We discuss how each of these approaches has been implemented across known genetic causes as well as sporadic ALS, reviewing preclinical studies as well as completed and ongoing human clinical trials. We highlight the transformative potential of these evolving technologies as the gene therapy field advances toward a true disease-modifying treatment for this devastating illness.
40Antisense Oligonucleotides for the Study and Treatment of ALS.PubMed
Benjamin D Boros, Kathleen M Schoch, Collin J Kreple, et al.
Neurotherapeutics. 2022 Jul;19(4):1145-1158. doi: 10.1007/s13311-022-01247-2. Epub 2022 Jun 2.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss. ALS is now associated with mutations in numerous genes, many of which cause disease in part through toxic gain-of-function mechanisms. Antisense oligonucleotides (ASOs) are small sequences of DNA that can reduce expression of a target gene at the post-transcriptional level, making them attractive for neutralizing mutant or toxic gene products. Advancements in the medicinal chemistries of ASOs have improved their pharmacodynamic profile to allow safe and effective delivery to the central nervous system. ASO therapies for ALS have rapidly developed over the last two decades, and ASOs that target SOD1, C9orf72, FUS, and ATXN2 are now in clinical trials for familial or sporadic forms of ALS. This review discusses the current state of ASO therapies for ALS, outlining their successes from preclinical development to early clinical trials.
41Gene therapy for neurological disorders: challenges and recent advancements.PubMed
Stefanie A Pena, Rahul Iyengar, Rebecca S Eshraghi, et al.
J Drug Target. 2020 Feb;28(2):111-128. doi: 10.1080/1061186X.2019.1630415. Epub 2019 Jul 11.
Major advancements in targeted gene therapy have opened up avenues for the treatment of major neurological disorders through a range of versatile modalities varying from expression of exogenous to suppression of endogenous genes. Recent technological innovations for improved gene sequence delivery have focussed on highly specific viral vector designs, plasmid transfection, nanoparticles, polymer-mediated gene delivery, engineered microRNA and clustered regulatory interspaced short palindromic repeats (CRISPR)-based therapeutics. These advanced techniques have profound applications in treating highly prevalent neurological diseases and neurodevelopmental disorders including Parkinson's disease, Alzheimer's disease and autism spectrum disorder, as well as rarer diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, lysosomal storage diseases, X-linked adrenoleukodystrophy and oncological diseases. In this article, we present an overview of the latest advances in targeted gene delivery and discuss the challenges and future direction of gene therapy in the treatment of neurological disorders.
42Gene therapy for CNS disorders: modalities, delivery and translational challenges.PubMed
Jingjing Gao, Swetharajan Gunasekar, Ziting Judy Xia, et al.
Nat Rev Neurosci. 2024 Aug;25(8):553-572. doi: 10.1038/s41583-024-00829-7. Epub 2024 Jun 19.
Gene therapy is emerging as a powerful tool to modulate abnormal gene expression, a hallmark of most CNS disorders. The transformative potentials of recently approved gene therapies for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and active cerebral adrenoleukodystrophy are encouraging further development of this approach. However, most attempts to translate gene therapy to the clinic have failed to make it to market. There is an urgent need not only to tailor the genes that are targeted to the pathology of interest but to also address delivery challenges and thereby maximize the utility of genetic tools. In this Review, we provide an overview of gene therapy modalities for CNS diseases, emphasizing the interconnectedness of different delivery strategies and routes of administration. Important gaps in understanding that could accelerate the clinical translatability of CNS genetic interventions are addressed, and we present lessons learned from failed clinical trials that may guide the future development of gene therapies for the treatment and management of CNS disorders.
43Cutting-edge treatments in amyotrophic lateral sclerosis: the role of molecular pathogenesis in targeted therapies.PubMed
Ramin Raoufinia, Ghazal Alyari, Amin Tadayoni Nia, et al.
Stem Cell Res Ther. 2025 Nov 23;16(1):689. doi: 10.1186/s13287-025-04781-w.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the selective loss of motor neurons (MNs), leading to progressive muscle weakness, atrophy, and ultimately paralysis. This review provides a comprehensive overview of the molecular mechanisms underlying ALS pathogenesis, the genetic mutations associated with both familial and sporadic forms of the disease, and the latest therapeutic strategies aimed at mitigating disease progression. mutations in genes such as C9orf72, SOD1, TARDBP, and FUS have been implicated in ALS, with an intricate interplay of protein misfolding, oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation contributing to motor neuron degeneration. While current FDA-approved treatments such as Riluzole and Edaravone offer only modest benefits and do not significantly halt disease progression. Emerging therapies, including gene therapies (e.g., antisense oligonucleotides (ASOs) and CRISPR/Cas9, stem cell-based approaches, and neurotrophic factor supplementation, are demonstrating promising results in preclinical and early-phase clinical trials. novel approaches aim to target, modulate, and promote regeneration, renewed hope for future ALS treatments. However, several challenges remain, including effective delivery methods, safety concerns, and the inherent complexity of ALS pathology, ongoing research continues to explore these innovative interventions with the goal of improving clinical outcomes for patients. This review highlights the importance of personalized therapeutic approaches and underscores the necessity of continued innovation in ALS research, with the ultimate goal of developing disease-modifying therapies and, potentially, a cure for this fatal condition.
44Mechanisms underlying inflammation in neurodegeneration.PubMed
Christopher K Glass, Kaoru Saijo, Beate Winner, et al.
Cell. 2010 Mar 19;140(6):918-34. doi: 10.1016/j.cell.2010.02.016.
Inflammation is associated with many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. In this Review, we discuss inducers, sensors, transducers, and effectors of neuroinflammation that contribute to neuronal dysfunction and death. Although inducers of inflammation may be generated in a disease-specific manner, there is evidence for a remarkable convergence in the mechanisms responsible for the sensing, transduction, and amplification of inflammatory processes that result in the production of neurotoxic mediators. A major unanswered question is whether pharmacological inhibition of inflammation pathways will be able to safely reverse or slow the course of disease.
45Glycometabolic Reprogramming of Microglia in Neurodegenerative Diseases: Insights from Neuroinflammation.PubMed
Qi Huang, Yanfu Wang, Shanshan Chen, et al.
Aging Dis. 2024 May 7;15(3):1155-1175. doi: 10.14336/AD.2023.0807.
Neurodegenerative diseases (ND) are conditions defined by progressive deterioration of the structure and function of the nervous system. Some major examples include Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). These diseases lead to various dysfunctions, like impaired cognition, memory, and movement. Chronic neuroinflammation may underlie numerous neurodegenerative disorders. Microglia, an important immunocell in the brain, plays a vital role in defending against neuroinflammation. When exposed to different stimuli, microglia are activated and assume different phenotypes, participating in immune regulation of the nervous system and maintaining tissue homeostasis. The immunological activity of activated microglia is affected by glucose metabolic alterations. However, in the context of chronic neuroinflammation, specific alterations of microglial glucose metabolism and their mechanisms of action remain unclear. Thus, in this paper, we review the glycometabolic reprogramming of microglia in ND. The key molecular targets and main metabolic pathways are the focus of this research. Additionally, this study explores the mechanisms underlying microglial glucose metabolism reprogramming in ND and offers an analysis of the most recent therapeutic advancements. The ultimate aim is to provide insights into the development of potential treatments for ND.
46Sex-Specific Markers of Neuroinflammation and Neurodegeneration in the Spinal Cord Proteome of the SOD1 Mouse Model of Amyotrophic Lateral Sclerosis.PubMed
Liam M Koehn, Joel R Steele, Ralf B Schittenhelm, et al.
J Proteome Res. 2025 Apr 4;24(4):1956-1970. doi: 10.1021/acs.jproteome.4c00990. Epub 2025 Mar 21.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that has no cure. The underlying mechanistic details of sex differences in the ALS spinal cord, the site of disease onset, are not understood to an extent that could guide novel drug development. To address this, the spinal cords of 120-day-old wild-type (WT) and SOD1 (familial mouse model of ALS with mutant superoxide dismutase 1) mice were subjected to untargeted, quantitative proteomics using tandem mass tag acquisition on high-resolution mass spectrometric instrumentation. Compared to WT, both male and female SOD1 spinal cords exhibited an upregulation of neuroinflammatory cascades of both peripheral and central origins, as well as a downregulation of proteins reflective of death and dysfunction of cells within the spinal cord. However, female and male SOD1 mouse spinal cords exhibited sex-specific differences in proteins compared to respective WT that related to immune response, as well as cellular structure, function, and homeostasis. The proteomic datasets presented provide entire cohort and sex-specific spinal cord drug targets and disease biomarkers in the SOD1 mouse model of ALS that may guide future drug development and sex selection in preclinical study designs utilizing the SOD1 model.
47Tauroursodeoxycholic acid: a potential therapeutic tool in neurodegenerative diseases.PubMed
Kareem Khalaf, Paolo Tornese, Antoniangela Cocco, et al.
Transl Neurodegener. 2022 Jun 4;11(1):33. doi: 10.1186/s40035-022-00307-z.
Most neurodegenerative disorders are diseases of protein homeostasis, with misfolded aggregates accumulating. The neurodegenerative process is mediated by numerous metabolic pathways, most of which lead to apoptosis. In recent years, hydrophilic bile acids, particularly tauroursodeoxycholic acid (TUDCA), have shown important anti-apoptotic and neuroprotective activities, with numerous experimental and clinical evidence suggesting their possible therapeutic use as disease-modifiers in neurodegenerative diseases. Experimental evidence on the mechanisms underlying TUDCA's neuroprotective action derives from animal models of Alzheimer's disease, Parkinson's disease, Huntington's diseases, amyotrophic lateral sclerosis (ALS) and cerebral ischemia. Preclinical studies indicate that TUDCA exerts its effects not only by regulating and inhibiting the apoptotic cascade, but also by reducing oxidative stress, protecting the mitochondria, producing an anti-neuroinflammatory action, and acting as a chemical chaperone to maintain the stability and correct folding of proteins. Furthermore, data from phase II clinical trials have shown TUDCA to be safe and a potential disease-modifier in ALS. ALS is the first neurodegenerative disease being treated with hydrophilic bile acids. While further clinical evidence is being accumulated for the other diseases, TUDCA stands as a promising treatment for neurodegenerative diseases.
48Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis.PubMed
A E Elia, S Lalli, M R Monsurrò, et al.
Eur J Neurol. 2016 Jan;23(1):45-52. doi: 10.1111/ene.12664. Epub 2015 Feb 9.
BACKGROUND AND PURPOSE: Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is produced in the liver and used for treatment of chronic cholestatic liver diseases. Experimental studies suggest that TUDCA may have cytoprotective and anti-apoptotic action, with potential neuroprotective activity. A proof of principle approach was adopted to provide preliminary data regarding the efficacy and tolerability of TUDCA in a series of patients with amyotrophic lateral sclerosis (ALS). METHODS: As a proof of principle, using a double-blind placebo controlled design, 34 ALS patients under treatment with riluzole who were randomized to placebo or TUDCA (1 g twice daily for 54 weeks) were evaluated after a lead-in period of 3 months. The patients were examined every 6 weeks. The primary outcome was the proportion of responders [those subjects with improvement of at least 15% in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) slope during the treatment period compared to the lead-in phase]. Secondary outcomes included between-treatment comparison of ALSFRS-R at study end, comparison of the linear regression slopes for ALSFFRS-R mean scores and the occurrence of adverse events. RESULTS: Tauroursodeoxycholic acid was well tolerated; there were no between-group differences for adverse events. The proportion of responders was higher under TUDCA (87%) than under placebo (P = 0.021; 43%). At study end baseline-adjusted ALSFRS-R was significantly higher (P = 0.007) in TUDCA than in placebo groups. Comparison of the slopes of regression analysis showed slower progression in the TUDCA than in the placebo group (P < 0.01). CONCLUSIONS: This pilot study provides preliminary clinical data indicating that TUDCA is safe and may be effective in ALS.
49Effects of PB-TURSO on the transcriptional and metabolic landscape of sporadic ALS fibroblasts.PubMed
Jasmine A Fels, Jalia Dash, Kent Leslie, et al.
Ann Clin Transl Neurol. 2022 Oct;9(10):1551-1564. doi: 10.1002/acn3.51648. Epub 2022 Sep 9.
OBJECTIVE: ALS is a rapidly progressive, fatal disorder caused by motor neuron degeneration, for which there is a great unmet therapeutic need. AMX0035, a combination of sodium phenylbutyrate (PB) and taurursodiol (TUDCA, TURSO), has shown promising results in early ALS clinical trials, but its mechanisms of action remain to be elucidated. Therefore, our goal was to obtain an unbiased landscape of the molecular effects of AMX0035 in ALS patient-derived cells. METHODS: We investigated the transcriptomic and metabolomic profiles of primary skin fibroblasts from sporadic ALS patients and healthy controls (n = 12/group) treated with PB, TUDCA, or PB-TUDCA combination (Combo). Data were evaluated with multiple approaches including differential gene expression and metabolite abundance, Gene Ontology and metabolic pathway analysis, weighted gene co-expression correlation analysis (WGCNA), and combined multiomics integrated analysis. RESULTS: Combo changed many more genes and metabolites than either PB or TUDCA individually. Most changes were unique to Combo and affected the expression of genes involved in nucleocytoplasmic transport, unfolded protein response, mitochondrial function, RNA metabolism, and innate immunity. WGCNA showed significant correlations between ALS gene expression modules and clinical parameters that were abolished by Combo treatment. INTERPRETATION: This study is the first to explore the molecular effects of Combo in ALS patient-derived cells. It shows that Combo has a greater and distinct impact compared with the individual compounds and provides clues to drug targets and mechanisms of action, which may underlie the benefits of this investigational drug combination.
50A Stem Cell-Based Screening Platform Identifies Compounds that Desensitize Motor Neurons to Endoplasmic Reticulum Stress.PubMed
Sebastian Thams, Emily Rhodes Lowry, Marie-Hélène Larraufie, et al.
Mol Ther. 2019 Jan 2;27(1):87-101. doi: 10.1016/j.ymthe.2018.10.010. Epub 2018 Oct 19.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease selectively targeting motor neurons in the brain and spinal cord. The reasons for differential motor neuron susceptibility remain elusive. We developed a stem cell-based motor neuron assay to study cell-autonomous mechanisms causing motor neuron degeneration, with implications for ALS. A small-molecule screen identified cyclopiazonic acid (CPA) as a stressor to which stem cell-derived motor neurons were more sensitive than interneurons. CPA induced endoplasmic reticulum stress and the unfolded protein response. Furthermore, CPA resulted in an accelerated degeneration of motor neurons expressing human superoxide dismutase 1 (hSOD1) carrying the ALS-causing G93A mutation, compared to motor neurons expressing wild-type hSOD1. A secondary screen identified compounds that alleviated CPA-mediated motor neuron degeneration: three kinase inhibitors and tauroursodeoxycholic acid (TUDCA), a bile acid derivative. The neuroprotective effects of these compounds were validated in human stem cell-derived motor neurons carrying a mutated SOD1 allele (hSOD1). Moreover, we found that the administration of TUDCA in an hSOD1 mouse model of ALS reduced muscle denervation. Jointly, these results provide insights into the mechanisms contributing to the preferential susceptibility of ALS motor neurons, and they demonstrate the utility of stem cell-derived motor neurons for the discovery of new neuroprotective compounds.
51Cox regression and survival analysis from the tauro-urso-deoxycholic trial in amyotrophic lateral sclerosis.PubMed
Giorgio Reggiardo, Maria Lo Giudice, Stefania Lalli, et al.
Front Neurol. 2023 Apr 20;14:1163855. doi: 10.3389/fneur.2023.1163855. eCollection 2023.
Recent phase II pilot clinical trials suggested that tauro-urso-deoxycholic acid (TUDCA) might slow functional decline and increase survival in patients with amyotrophic lateral sclerosis (ALS). We performed a multivariate analysis of the original TUDCA cohort to better define the treatment effect and allow comparability with other trials. Linear regression slope analysis showed statistical differences in the decline rate, favoring the active treatment arm (-value < 0.01; -0.262 for the TUDCA group and -0.388 for the placebo group). Mean survival time, estimated by the Kaplan-Meier analysis, showed a 1-month difference, favoring active treatment (log-rank test -value = 0.092). Cox regression analysis demonstrated that placebo treatment was associated with a higher risk of death (-value = 0.055). These data further support the disease-modifying effect of TUDCA monotherapy and raise the question of what could be the additional effect of combining TUDCA with sodium phenylbutyrate.
52A randomized double-blind clinical trial on safety and efficacy of tauroursodeoxycholic acid (TUDCA) as add-on treatment in patients affected by amyotrophic lateral sclerosis (ALS): the statistical analysis plan of TUDCA-ALS trial.PubMed
Flavia L Lombardo, Stefania Spila Alegiani, Flavia Mayer, et al.
Trials. 2023 Dec 5;24(1):792. doi: 10.1186/s13063-023-07638-w.
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a highly debilitating neurodegenerative condition. Despite recent advancements in understanding the molecular mechanisms underlying ALS, there have been no significant improvements in therapeutic options for ALS patients in recent years. Currently, there is no cure for ALS, and the only approved treatment in Europe is riluzole, which has been shown to slow the disease progression and prolong survival by approximately 3 months. Recently, tauroursodeoxycholic acid (TUDCA) has emerged as a promising and effective treatment for neurodegenerative diseases due to its neuroprotective activities. METHODS: The ongoing TUDCA-ALS study is a double-blinded, parallel arms, placebo-controlled, randomized multicenter phase III trial with the aim to assess the efficacy and safety of TUDCA as add-on therapy to riluzole in patients with ALS. The primary outcome measure is the treatment response defined as a minimum of 20% improvement in the ALS Functional Rating Scale-Revised (ALSFRS-R) slope during the randomized treatment period (18 months) compared to the lead-in period (3 months). Randomization will be stratified by country. Primary analysis will be conducted based on the intention-to-treat principle through an unadjusted logistic regression model. Patient recruitment commenced on February 22, 2019, and was closed on December 23, 2021. The database will be locked in September 2023. DISCUSSION: This paper provides a comprehensive description of the statistical analysis plan in order to ensure the reproducibility of the analysis and avoid selective reporting of outcomes and data-driven analysis. Sensitivity analyses have been included in the protocol to assess the impact of intercurrent events related to the coronavirus disease 2019. By focusing on clinically meaningful and robust outcomes, this trial aims to determine whether TUDCA can be effective in slowing the disease progression in patients with ALS. TRIAL REGISTRATION: ClinicalTrials.gov NCT03800524 . Registered on January 11, 2019.
53Tauroursodeoxycholic acid in patients with amyotrophic lateral sclerosis: The TUDCA-ALS trial protocol.PubMed
Alberto Albanese, Albert Christian Ludolph, Christopher J McDermott, et al.
Front Neurol. 2022 Sep 27;13:1009113. doi: 10.3389/fneur.2022.1009113. eCollection 2022.
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative rare disease that affects motor neurons in the brain, brainstem, and spinal cord, resulting in progressive weakness and atrophy of voluntary skeletal muscles. Although much has been achieved in understanding the disease pathogenesis, treatment options are limited, and in Europe, riluzole is the only approved drug. Recently, some other drugs showed minor effects. METHODS: The TUDCA-ALS trial is a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The study aims to enroll 320 patients in 25 centers across seven countries in Europe. Enrolled patients are randomized to one of two treatment arms: TUDCA or identical placebo by oral route. The study measures disease progression during the treatment period and compares it to natural progression during a no-treatment run-in phase. Clinical data and specific biomarkers are measured during the trial. The study is coordinated by a consortium composed of leading European ALS centers. CONCLUSION: This trial is aimed to determine whether TUDCA has a disease-modifying activity in ALS. Demonstration of TUDCA efficacy, combined with the validation of new biomarkers, could advance ALS patient care. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT03800524.
54Sodium Phenylbutyrate and Tauroursodeoxycholic Acid: A Story of Hope Turned to Disappointment in Amyotrophic Lateral Sclerosis Treatment.PubMed
Arsh Ketabforoush, Faezeh Faghihi, Fereshteh Azedi, et al.
Clin Drug Investig. 2024 Jul;44(7):495-512. doi: 10.1007/s40261-024-01371-1. Epub 2024 Jun 23.
The absence of a definitive cure for amyotrophic lateral sclerosis (ALS) emphasizes the crucial need to explore new and improved treatment approaches for this fatal, progressive, and disabling neurodegenerative disorder. As at the end of 2023, five treatments - riluzole, edaravone, dextromethorphan hydrobromide + quinidine sulfate (DHQ), tofersen, and sodium phenylbutyrate-tauroursodeoxycholic acid (PB-TUDCA) - were FDA approved for the treatment of patients with ALS. Among them PB-TUDCA has been shown to impact DNA processing impairments, mitochondria dysfunction, endoplasmic reticulum stress, oxidative stress, and pathologic folded protein agglomeration defects, which have been associated with ALS pathophysiology. The Phase 2 CENTAUR trial demonstrated significant impact of PB-TUDCA on the ALS Functional Rating Scale-Revised (ALSFRS-R) risk of death, hospitalization, and the need for tracheostomy or permanent assisted ventilation in patients with ALS based on post hoc analyses. More recently, contrasting with the CENTAUR trial results, results from the Phase 3 PHOENIX trial (NCT05021536) showed no change in ALSFRS-R total score at 48 weeks. Consequently, the sponsor company initiated the process with the US FDA and Health Canada to voluntarily withdraw the marketing authorizations for PB-TUDCA. In the present article, we review ALS pathophysiology, with a focus on PB-TUDCA's proposed mechanisms of action and recent clinical trial results and discuss the implications of conflicting trial data for ALS and other neurological disorders.
55Treatment for sialorrhea (excessive saliva) in people with motor neuron disease/amyotrophic lateral sclerosis.PubMed
Eleanor James, Cathy Ellis, Ruth Brassington, et al.
Cochrane Database Syst Rev. 2022 May 20;5(5):CD006981. doi: 10.1002/14651858.CD006981.pub3.
BACKGROUND: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative condition that may cause dysphagia, as well as limb weakness, dysarthria, emotional lability, and respiratory failure. Since normal salivary production is 0.5 L to 1.5 L daily, loss of salivary clearance due to dysphagia leads to salivary pooling and sialorrhea, often resulting in distress and inconvenience to people with MND. This is an update of a review first published in 2011. OBJECTIVES: To assess the effects of treatments for sialorrhea in MND, including medications, radiotherapy and surgery. SEARCH METHODS: On 27 August 2021, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, AMED, CINAHL, ClinicalTrials.gov and the WHO ICTRP. We checked the bibliographies of the identified randomized trials and contacted trial authors as needed. We contacted known experts in the field to identify further published and unpublished papers. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs, including cross-over trials, on any intervention for sialorrhea and related symptoms, compared with each other, placebo or no intervention, in people with ALS/MND. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified four RCTs involving 110 participants with MND who were described as having intractable sialorrhea or bulbar dysfunction. A well-designed study of botulinum toxin B compared to placebo injected into the parotid and submandibular glands of 20 participants showed that botulinum toxin B may produce participant-reported improvement in sialorrhea, but the confidence interval (CI) was also consistent with no effect. Six of nine participants in the botulinum group and two of nine participants in the placebo group reported improvement (risk ratio (RR) 3.00, 95% CI 0.81 to 11.08; 1 RCT; 18 participants; low-certainty evidence). An objective measure indicated that botulinum toxin B probably reduced saliva production (in mL/5 min) at eight weeks compared to placebo (MD -0.50, 95% CI -1.07 to 0.07; 18 participants, moderate-certainty evidence). Botulinum toxin B may have little to no effect on quality of life, measured on the Schedule for Evaluation of Individual Quality of Life direct weighting scale (SEIQoL-DW; 0-100, higher values indicate better quality of life) (MD -2.50, 95% CI -17.34 to 12.34; 1 RCT; 17 participants; low-certainty evidence). The rate of adverse events may be similar with botulinum toxin B and placebo (20 participants; low-certainty evidence). Trialists did not consider any serious events to be related to treatment. A randomized pilot study of botulinum toxin A or radiotherapy in 20 participants, which was at high risk of bias, provided very low-certainty evidence on the primary outcome of the Drool Rating Scale (DRS; range 8 to 39 points, higher scores indicate worse drooling) at 12 weeks (effect size -4.8, 95% CI -10.59 to 0.92; P = 0.09; 1 RCT; 16 participants). Quality of life was not measured. Evidence for adverse events, measured immediately after treatment (RR 7.00, 95% CI 1.04 to 46.95; 20 participants), and after four weeks (when two people in each group had viscous saliva) was also very uncertain. A phase 2, randomized, placebo-controlled cross-over study of 20 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate (DMQ) found that DMQ may produce a participant-reported improvement in sialorrhea, indicated by a slight improvement (decrease) in mean scores for the primary outcome, the Center for Neurologic Study Bulbar Function Scale (CNS-BFS). Mean total CNS-BFS (range 21 (no symptoms) to 112 (maximum symptoms)) was 53.45 (standard error (SE) 1.07) for the DMQ treatment period and 59.31 (SE 1.10) for the placebo period (mean difference) MD -5.85, 95% CI -8.77 to -2.93) with a slight decrease in the CNS-BFS sialorrhea subscale score (range 7 (no symptoms) to 35 (maximum symptoms)) compared to placebo (MD -1.52, 95% CI -2.52 to -0.52) (1 RCT; 60 participants; moderate-certainty evidence). The trial did not report an objective measure of saliva production or measure quality of life. The study was at an unclear risk of bias. Adverse events were similar to other trials of DMQ, and may occur at a similar rate as placebo (moderate-certainty evidence, 60 participants), with the most common side effects being constipation, diarrhea, nausea, and dizziness. Nausea and diarrhea on DMQ treatment resulted in one withdrawal. A randomized, double-blind, placebo-controlled cross-over study of scopolamine (hyoscine), administered using a skin patch, involved 10 randomized participants, of whom eight provided efficacy data. The participants were unrepresentative of clinic cohorts under routine clinical care as they had feeding tubes and tracheostomy ventilation, and the study was at high risk of bias. The trial provided very low-certainty evidence on sialorrhea in the short term (7 days' treatment, measured on the Amyotrophic Lateral Scelerosis Functional Rating Scale-Revised (ALSFRS-R) saliva item (P = 0.572)), and the amount of saliva production in the short term, as indicated by the weight of a cotton roll (P = 0.674), or daily oral suction volume (P = 0.69). Quality of life was not measured. Adverse events evidence was also very uncertain. One person treated with scopolamine had a dry mouth and one died of aspiration pneumonia considered unrelated to treatment. AUTHORS' CONCLUSIONS: There is some low-certainty or moderate-certainty evidence for the use of botulinum toxin B injections to salivary glands and moderate-certainty evidence for the use of oral dextromethorphan with quinidine (DMQ) for the treatment of sialorrhea in MND. Evidence on radiotherapy versus botulinum toxin A injections, and scopolamine patches is too uncertain for any conclusions to be drawn. Further research is required on treatments for sialorrhea. Data are needed on the problem of sialorrhea in MND and its measurement, both by participant self-report measures and objective tests. These will allow the development of better RCTs.
56Botulinum Toxin Treatment of Autonomic Disorders: Focal Hyperhidrosis and Sialorrhea.PubMed
Christine Hosp, Markus K Naumann, Henning Hamm
Semin Neurol. 2016 Feb;36(1):20-8. doi: 10.1055/s-0035-1571214. Epub 2016 Feb 11.
Primary focal hyperhidrosis is a common autonomic disorder that significantly impacts quality of life. It is characterized by excessive sweating confined to circumscribed areas, such as the axillae, palms, soles, and face. Less frequent types of focal hyperhidrosis secondary to underlying causes include gustatory sweating in Frey's syndrome and compensatory sweating in Ross' syndrome and after sympathectomy. Approval of onabotulinumtoxinA for severe primary axillary hyperhidrosis in 2004 has revolutionized the treatment of this indication. Meanwhile further type A botulinum neurotoxins like abobotulinumtoxinA and incobotulinumtoxinA, as well as the type B botulinum neurotoxin rimabotulinumtoxinB are successfully used off-label for axillary and various other types of focal hyperhidrosis. For unexplained reasons, the duration of effect differs considerably at different sites. Beside hyperhidrosis, botulinum neurotoxin is also highly valued for the treatment of sialorrhea affecting patients with Parkinson's disease, cerebral palsy, amyotrophic lateral sclerosis, motor neuron disease, and other neurologic conditions. With correct dosing and application, side effects are manageable and transient.
57[Treatment of sialorrhea with botulinum toxin: an overview].PubMed
J Hagenah, K G Kahl, S Steinlechner, et al.
Nervenarzt. 2005 Apr;76(4):418-25. doi: 10.1007/s00115-004-1799-z.
Hypersalivation (sialorrhea) is a common complaint of patients with neurodegenerative disorders such as Parkinson's disease or amyotrophic lateral sclerosis and a frequently disabling side effect of atypical antipsychotic drugs. Conventional treatment including oral anticholinergic or antihistamine medication is often limited by adverse effects and lack of efficacy. Over the past few years, several studies reported decreased drooling after injections of botulinum toxin into the salivary glands. This review describes the current state of treatment of sialorrhea with botulinum toxin.
58Pharmacological interventions for treating sialorrhea associated with neurological disorders: A mixed treatment network meta-analysis of randomized controlled trials.PubMed
Kannan Sridharan, Gowri Sivaramakrishnan
J Clin Neurosci. 2018 May;51:12-17. doi: 10.1016/j.jocn.2018.02.011. Epub 2018 Feb 21.
Sialorrhea is a common distress associated with certain neurological disorders. The aim of this study is to compare the pharmacological agents used for treating sialorrhea by network meta-analysis. Electronic databases were searched for randomized clinical trials comparing active drugs with either placebo or other active drugs. Total drooling scores was the primary outcome measure. Inverse variance heterogeneity model was used for both direct and mixed treatment comparison analysis. Twenty one studies were included in the systematic review and 15 in the meta-analysis. Compared to placebo, benztropine, botulinum toxins A and B are associated with a significant reduction in the frequency and severity of drooling both in the overall neurological disorders as well as for children with cerebral palsy. Only botulinum toxin A and B were associated with significant therapeutic effects in Parkinson's disease. Benztropine and botulinum toxins A and B were observed to be effective in reducing sialorrhea associated with neurological disorders.
59Salivary gland application of botulinum toxin for the treatment of sialorrhea.PubMed
María Angeles Fuster Torres, Leonardo Berini Aytés, Cosme Gay Escoda
Med Oral Patol Oral Cir Bucal. 2007 Nov 1;12(7):E511-7.
Sialorrhea or excessive salivation, and drooling, are common and disabling manifestations in different neurological disorders. A review is made of the literature, based on a PubMed search, selecting those articles describing clinical trials involving the injection of botulinum toxin A in the salivary glands of patients with different diseases characterized by sialorrhea. The most frequently treated diseases were infant cerebral palsy (30%), Parkinson's disease (20%) and amyotrophic lateral sclerosis (15%). Over half of the authors injected the product into the parotid glands, 9.5% into the submaxillary glands, and 38% into both. The total doses of toxin injected varied from 10-100 units of Botox or 30-450 units of Dysport according to the different authors. A reduction was observed in the production of saliva following these injections, and the duration of the therapeutic effect was 1.5-6 months. Six articles (30%) described the presence of adverse effects such as dysphagia, xerostomia and chewing difficulties. Most of the clinical studies involved small patient samples, with no blinding or randomization, and no control group. Moreover, no data are available on the efficacy and adverse effects of treatment in the context of long-term prospective studies. The effective therapeutic dose and ideal form of application remain to be established, and require the conduction of further controlled clinical trials involving large sample sizes.
60Botulinum Toxin A and B in sialorrhea: Long-term data and literature overview.PubMed
Martina Petracca, Arianna Guidubaldi, Lucia Ricciardi, et al.
Toxicon. 2015 Dec 1;107(Pt A):129-40. doi: 10.1016/j.toxicon.2015.08.014. Epub 2015 Aug 30.
INTRODUCTION AND OBJECTIVES: In recent years, Botulinum Toxin has been shown to be efficacious and safe in the treatment of sialorrhea, but scanty data are available on its long term use. The aim of this study was to investigate adverse events, discriminate differences in safety, and evaluate the efficacy of long-term use of both abobotulinumtoxinA and rimabotulinumtoxinB ultrasound-guided injections for sialorrhea in a retrospective trial. Moreover we review the literature on this topic. PATIENTS AND METHODS: Consecutive patients with severe sialorrhea and receiving at least two ultrasound-guided intrasalivary glands abobotulinumtoxinA 250 U or rimabotulinumtoxinB 2500 U injections were included. Clinical and demographic data were collected. Safety and tolerability were assessed on the basis of patients' self-reports. Efficacy was assessed by recording the duration of benefit and by the Drooling Severity Scale and Drooling Frequency Scale 4 weeks after intervention. A review of literature was performed using 'Botulinum Toxin' and/or 'drooling' and/or 'sialorrhea' and/or 'hypersalivation' as keywords. RESULTS: Sixty-five patients (32 Amyotrophic Lateral Sclerosis and 33 Parkinson's Disease) were treated in a total of 317 sessions (181 rimabotulinumtoxinB and 136 abobotulinumtoxinA). Both serotypes induced a clear-cut benefit in 89% of injections. Mean benefit duration was 87 days (range 30-240), similar for abobotulinumtoxinA and rimabotulinumtoxinB but significantly shorter in Amyotrophic Lateral Sclerosis group compared to Parkinson's Disease (p < 0.001). Older age was positively correlated to benefit duration (p = 0.003). Botulinum Toxin-related and injection-related side effects complicated respectively 8,2% and 1,5% of treatments. The only Botulinum Toxin-related adverse event was a change of saliva thickness, mostly rated mild to moderate and more frequent in Amyotrophic Lateral Sclerosis patients (p = NS). CONCLUSIONS: Both 250 U abobotulinumtoxinA and 2500 U rimabotulinumtoxinB administered by ultrasound-guided intrasalivary gland injection are safe and effective in treating sialorrhea, even in long-term follow-up. Older age is significantly associated with longer benefit duration. Parkinson's Disease patients showed a more favorable safety-efficacy ratio than did Amyotrophic Lateral Sclerosis patients, due to lower adverse events (p = NS) and longer benefit duration (p < 0.001).
61Efficacy and Safety of IncobotulinumtoxinA for Treatment of Sialorrhea: A Multicenter, Phase 3 Study in Japan.PubMed
Nobutaka Hattori, Yohei Mukai, Noriko Nishikawa, et al.
Mov Disord Clin Pract. 2025 Aug 7. doi: 10.1002/mdc3.70259.
BACKGROUND: Sialorrhea, caused by various neurological diseases, impairs patient health and quality of life. After the results of a randomized controlled trial, incobotulinumtoxinA was approved for the treatment of chronic sialorrhea in the United States and Europe; however, no pharmacotherapy has been approved in Japan. OBJECTIVE: The aim was to evaluate the efficacy and safety of incobotulinumtoxinA treatment for chronic sialorrhea in a single-arm phase 3 study in Japan. METHODS: Patients with chronic sialorrhea caused by neurological diseases (Parkinson's disease, atypical parkinsonism, and stroke, group A) and broader diseases (eg, muscular dystrophy and amyotrophic lateral sclerosis, group B) were enrolled. IncobotulinumtoxinA 100 U was injected into the salivary glands once every 16 weeks for 48 weeks. A primary endpoint was assessed in group A, whereas secondary endpoints and safety were assessed in both groups. RESULTS: From November 2021 to August 2023, 92 patients (58 and 34 in groups A and B, respectively) received incobotulinumtoxinA at 28 institutions. The primary endpoint, the least square mean (standard error) of change in unstimulated salivary flow rate from baseline to 4 weeks, was -0.08 (0.009, 95% confidence interval [CI]: -0.10, -0.06) g/min, achieving the prespecified efficacy criteria (upper limit of the 95% CI <-0.04). The secondary endpoints were consistent across efficacy measures, indicating that reduced salivary secretion and improved drooling symptoms persisted for 48 weeks. The most common adverse events were dry mouth and dysphagia. CONCLUSIONS: The first study in Japan confirmed the efficacy of incobotulinumtoxinA treatment for chronic sialorrhea with good patient tolerability and no new safety concerns.
62Safety and Efficacy of RimabotulinumtoxinB for Treatment of Sialorrhea in Adults: A Randomized Clinical Trial.PubMed
Stuart H Isaacson, William Ondo, Carlayne E Jackson, et al.
JAMA Neurol. 2020 Apr 1;77(4):461-469. doi: 10.1001/jamaneurol.2019.4565.
IMPORTANCE: RimabotulinumtoxinB (RIMA) may be preferable as an anti-sialorrhea treatment compared with current oral anticholinergic drugs in people with neurological disorders. OBJECTIVE: To assess the safety, efficacy, and tolerability of RIMA injections for the treatment of sialorrhea in adults. DESIGN, SETTING, AND PARTICIPANTS: This randomized, parallel, double-blind, placebo-controlled clinical trial of RIMA 2500 U and 3500 U was conducted from November 14, 2013, to January 23, 2017. A total of 249 adult patients with troublesome sialorrhea secondary to any disorder or cause were screened. Of them, 13 refused further participation in the study or were lost to follow-up and 49 did not fulfill the criteria for participation; 187 were ultimately enrolled. Patients had to have a minimum unstimulated salivary flow rate (USFR) of 0.2 g/min and a minimum Drooling Frequency and Severity Scale score of 4. EXPOSURES: Patients were randomized 1:1:1 to RIMA, 2500 U (n = 63); RIMA, 3500 U (n = 64); or placebo (n = 60). MAIN OUTCOMES AND MEASURES: Primary outcomes were the change in USFR from baseline to week 4 and the Clinical Global Impression of Change (CGI-C) at week 4. The CGI-C scores were recorded on a 7-point scale ranging from very much improved to very much worse. Adverse events were recorded throughout the trial period. RESULTS: Of 187 patients enrolled (147 men [78.6%]; mean [SD] age, 63.9 [13.3] years), 122 patients had Parkinson disease (65.2%), 13 (7.0%) were stroke survivors, 12 had amyotrophic lateral sclerosis (6.4%), 6 had medication-induced sialorrhea (3.2%), 4 had adult cerebral palsy (2.1%), and 30 had sialorrhea owing to other causes (16.0%). A total of 176 completed the study. Treatment with both doses of RIMA significantly reduced USFR at week 4 vs placebo (mean treatment difference, -0.30 g/min [95% CI, -0.39 to -0.21] for both doses vs placebo, P < .001). The CGI-C scores were statistically significantly improved at week 4 for both treatment groups vs placebo (-1.21 [95% CI, -1.56 to -0.87] for 2500 U, -1.14 [95% CI, -1.49 to -0.80] for 3500 U, both P < .001). Treatment benefits were seen as early as 1 week after injection and were maintained over the treatment cycle of approximately 13 weeks. The RIMA injections were well tolerated compared with placebo. The most common adverse events were self-limited mild to moderate dry mouth, dysphagia, and dental caries. CONCLUSIONS AND RELEVANCE: Treatment with RIMA (2500 U and 3500 U) in adults was well tolerated and reduced sialorrhea, with the onset of the effect at 1 week after the injection. These data support the clinical use of RIMA in the management of sialorrhea in adults. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01994109.
63Enhanced Bulbar Function in Amyotrophic Lateral Sclerosis: The Nuedexta Treatment Trial.PubMed
Richard Smith, Erik Pioro, Kathleen Myers, et al.
Neurotherapeutics. 2017 Jul;14(3):762-772. doi: 10.1007/s13311-016-0508-5.
The goal of this randomized, blinded, crossover clinical trial was to determine whether Nuedexta (dextromethorphan and quinidine) enhanced speech, swallowing, and salivation in patients with ALS. Sixty patients with amyotrophic lateral sclerosis (ALS) received either Nuedexta or placebo for 28 to 30 days, followed by a 10 to 15-day washout period. Subsequently, patients were switched to the opposite treatment arm for the remaining days of the trial. The primary endpoint was a reduction in the self-report Center for Neurologic Study Bulbar Function Scale (CNS-BFS) score. The rater-administered ALS Functional Rating Scale Revised was the principal secondary endpoint. The CNS-BFS score improved with active treatment, decreasing from a mean of 59.3 in the placebo arm of the trial to 53.5 during the drug-treatment arm (p < 0.001). Each of the individual domains of bulbar function interrogated by the CNS-BFS responded to treatment with Nuedexta as follows: salivation: 15.8 versus 14.3 (p = 0.004); speech: 24.6 versus 22.2 (p = 0.003); swallowing: 18.9 versus 17.1 (p = 0.009). Similarly, the bulbar component of the ALS Functional Rating Scale Revised improved with active treatment (p = 0.003), although the drug did not affect the motor and respiratory components of this scale. This study is unique for several reasons. Firstly, it was driven by patient reports of improved speech and swallowing while taking Nuedexta for control of emotional lability. Secondly, the study was conducted over a short duration (70 days), and thirdly, a self-report scale was selected as the principle outcome measure. Considering the importance of bulbar functions, these results, if confirmed, point to an additional use of Nuedexta as an adjunct to the management of ALS.
64Comparison of radiotherapy types in the treatment of sialorrhea in amyotrophic lateral sclerosis.PubMed
Nathalie Guy, Natacha Bourry, Radhouane Dallel, et al.
J Palliat Med. 2011 Apr;14(4):391-5. doi: 10.1089/jpm.2010.0308. Epub 2011 Mar 17.
OBJECTIVES: Many patients with amyotrophic lateral sclerosis (ALS) develop progressive difficulty swallowing secretions, leading to drooling. Although external beam radiation is considered to be an effective and well-tolerated treatment, the optimum schedule in terms of dose, target, radiation type, and number of fractions is unknown. The aim of this observational study was to define the most effective schedule for salivary gland irradiation and to compare electron and photon radiotherapy. METHODS: Sixteen patients with ALS (12 females and 4 males) with drooling, enrolled for external radiation of salivary glands between 2002 and 2007, were included. Patients received different treatment protocols according to the decision of their radiotherapist. Efficacy and safety were assessed at 1 and 6 months after treatment by a neurologist and a radiotherapist using a 4-point Likert patient improvement scale, as follows: 0 (no change), 1 (slight improvement), 2 (good improvement), and 3 (very good improvement). RESULTS: Radiotherapy for drooling was shown to be safe and effective in ALS patients with duration of effect expected up to 6 months. Eighty percent of patients felt improved at 1 month and 43% at 6 months after external radiation. Patients with sustained improvement at 6 months were treated with electron therapy (>8 MeV; p = 0.02). CONCLUSIONS: Electron-based radiotherapy, delivered as five 4Gy fractions to a total dose of 20 Gy, encompassing the whole of the submandibular gland and sparing the upper part of the parotid gland, can be proposed as a safe and effective schedule for the treatment of sialorrhea in patients with ALS.
65Care management in amyotrophic lateral sclerosis.PubMed
M-H Soriani, C Desnuelle
Rev Neurol (Paris). 2017 May;173(5):288-299. doi: 10.1016/j.neurol.2017.03.031. Epub 2017 Apr 29.
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative disease characterized by progressive weakness of voluntary muscles of movement as well as those for swallowing, speech and respiration. In the absence of curative treatment, care can improve quality of life, prolong survival, and support ALS patients and their families, and also help them to anticipate and prepare for the end of life. Multidisciplinary management in tertiary centers is recommended in close collaboration with general practitioners, home carers and a dedicated health network. Patients' follow-up deals mainly with motor impairment and physical disability, adaptation, nutrition and respiratory function. Involvement of palliative care as part of the multidisciplinary team management offers patients the possibility of discussing their end of life issues. This review summarizes the different aspects of ALS care, from delivering the diagnosis to the end of life, and the organization of its management.
66Mechanical ventilation for amyotrophic lateral sclerosis/motor neuron disease.PubMed
Aleksandar Radunovic, Djillali Annane, Muhammad K Rafiq, et al.
Cochrane Database Syst Rev. 2017 Oct 6;10(10):CD004427. doi: 10.1002/14651858.CD004427.pub4.
BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is a fatal neurodegenerative disease. Neuromuscular respiratory failure is the most common cause of death, which usually occurs within two to five years of the disease onset. Supporting respiratory function with mechanical ventilation may improve survival and quality of life. This is the second update of a review first published in 2009. OBJECTIVES: To assess the effects of mechanical ventilation (tracheostomy-assisted ventilation and non-invasive ventilation (NIV)) on survival, functional measures of disease progression, and quality of life in ALS, and to evaluate adverse events related to the intervention. SEARCH METHODS: We searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL Plus, and AMED on 30 January 2017. We also searched two clinical trials registries for ongoing studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs involving non-invasive or tracheostomy-assisted ventilation in participants with a clinical diagnosis of ALS, independent of the reported outcomes. We included comparisons with no intervention or the best standard care. DATA COLLECTION AND ANALYSIS: For the original review, four review authors independently selected studies for assessment. Two review authors reviewed searches for this update. All review authors independently extracted data from the full text of selected studies and assessed the risk of bias in studies that met the inclusion criteria. We attempted to obtain missing data where possible. We planned to collect adverse event data from the included studies. MAIN RESULTS: For the original Cochrane Review, the review authors identified two RCTs involving 54 participants with ALS receiving NIV. There were no new RCTs or quasi-RCTs at the first update. One new RCT was identified in the second update but was excluded for the reasons outlined below.Incomplete data were available for one published study comparing early and late initiation of NIV (13 participants). We contacted the trial authors, who were not able to provide the missing data. The conclusions of the review were therefore based on a single study of 41 participants comparing NIV with standard care. Lack of (or uncertain) blinding represented a risk of bias for participant- and clinician-assessed outcomes such as quality of life, but it was otherwise a well-conducted study with a low risk of bias.The study provided moderate-quality evidence that overall median survival was significantly different between the group treated with NIV and the standard care group. The median survival in the NIV group was 48 days longer (219 days compared to 171 days for the standard care group (estimated 95% confidence interval 12 to 91 days, P = 0.0062)). This survival benefit was accompanied by an enhanced quality of life. On subgroup analysis, in the subgroup with normal to moderately impaired bulbar function (20 participants), median survival was 205 days longer (216 days in the NIV group versus 11 days in the standard care group, P = 0.0059), and quality of life measures were better than with standard care (low-quality evidence). In the participants with poor bulbar function (21 participants), NIV did not prolong survival or improve quality of life, although there was significant improvement in the mean symptoms domain of the Sleep Apnea Quality of Life Index by some measures. Neither trial reported clinical data on intervention-related adverse effects. AUTHORS' CONCLUSIONS: Moderate-quality evidence from a single RCT of NIV in 41 participants suggests that it significantly prolongs survival, and low-quality evidence indicates that it improves or maintains quality of life in people with ALS. Survival and quality of life were significantly improved in the subgroup of people with better bulbar function, but not in those with severe bulbar impairment. Adverse effects related to NIV should be systematically reported, as at present there is little information on this subject. More RCT evidence to support the use of NIV in ALS will be difficult to generate, as not offering NIV to the control group is no longer ethically justifiable. Future studies should examine the benefits of early intervention with NIV and establish the most appropriate timing for initiating NIV in order to obtain its maximum benefit. The effect of adding cough augmentation techniques to NIV also needs to be investigated in an RCT. Future studies should examine the health economics of NIV. Access to NIV remains restricted in many parts of the world, including Europe and North America. We need to understand the factors, personal and socioeconomic, that determine access to NIV.
67Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial.PubMed
Stephen C Bourke, Mark Tomlinson, Tim L Williams, et al.
Lancet Neurol. 2006 Feb;5(2):140-7. doi: 10.1016/S1474-4422(05)70326-4.
BACKGROUND: Few patients with amyotrophic lateral sclerosis currently receive non-invasive ventilation (NIV), reflecting clinical uncertainty about the role of this intervention. We aimed to assess the effect of NIV on quality of life and survival in amyotrophic lateral sclerosis in a randomised controlled trial. METHODS: 92 of 102 eligible patients participated. They were assessed every 2 months and randomly assigned to NIV (n=22) or standard care (n=19) when they developed either orthopnoea with maximum inspiratory pressure less than 60% of that predicted or symptomatic hypercapnia. Primary validated quality-of-life outcome measures were the short form 36 mental component summary (MCS) and the sleep apnoea quality-of-life index symptoms domain (sym). Both time maintained above 75% of baseline (T(i)MCS and T(i)sym) and mean improvement (microMCS and microsym) were measured. FINDINGS: NIV improved T(i)MCS, T(i)sym, microMCS, microsym, and survival in all patients and in the subgroup with better bulbar function (n=20). This subgroup showed improvement in several measures of quality of life and a median survival benefit of 205 days (p=0.006) with maintained quality of life for most of this period. NIV improved some quality-of-life indices in those with poor bulbar function, including microsym (p=0.018), but conferred no survival benefit. INTERPRETATION: In patients with amyotrophic lateral sclerosis without severe bulbar dysfunction, NIV improves survival with maintenance of, and improvement in, quality of life. The survival benefit from NIV in this group is much greater than that from currently available neuroprotective therapy. In patients with severe bulbar impairment, NIV improves sleep-related symptoms, but is unlikely to confer a large survival advantage.
68Non-invasive ventilation in amyotrophic lateral sclerosis.PubMed
Bart Vrijsen, Dries Testelmans, Catharina Belge, et al.
Amyotroph Lateral Scler Frontotemporal Degener. 2013 Mar;14(2):85-95. doi: 10.3109/21678421.2012.745568. Epub 2013 Jan 4.
Abstract Non-invasive ventilation (NIV) is widely used to improve alveolar hypoventilation in amyotrophic lateral sclerosis. Several studies indicate a better survival when NIV is used, certainly in patients with none to moderate bulbar dysfunction. Data on quality of life (QoL) are rather disputable. Overall QoL is shown to be equivalent in patients with or without NIV, although health-related QoL is shown to be increased in patients with none to moderate bulbar dysfunction. NIV improves sleep quality, although patient-ventilator asynchronies are demonstrated. FVC < 50%, seated or supine, has been widely applied as threshold to initiate NIV. Today, measurements of respiratory muscle strength, nocturnal gas exchange and symptomatic complaints are used as indicators to start NIV. Being compliant with NIV therapy increases QoL and survival. Cough augmentation has an important role in appropriate NIV. Patients have today more technical options and patients with benefit from these advances are growing in number. Tracheal ventilation needs to be discussed when NIV seems impossible or becomes insufficient.
69Impact of Early Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis: A multicenter Randomized Controlled Trial.PubMed
Mikel Sarasate, Nuria González, Ana Córdoba-Izquierdo, et al.
J Neuromuscul Dis. 2023;10(4):627-637. doi: 10.3233/JND-221658.
BACKGROUND AND OBJECTIVE: Forced vital capacity (FVC) less than 50% of predicted is one of the main parameters used for Non-Invasive Ventilation (NIV) initiation in Amyotrophic Lateral Sclerosis (ALS). Recent studies suggest that higher values of FVC could be considered as a threshold. The aim of this study is to evaluate whether early use of NIV improves the prognosis of ALS patients compared with standard initiation. METHODS: This is a randomized, parallel, multicenter, open-label, controlled clinical trial, with recruitment at the ALS outpatient multidisciplinary units of six Spanish hospitals. Patients were included when their FVC reached the 75% threshold and were randomized by computer, stratifying by center in an allocation ratio of 1:1 to Early NIV (FVC below 75%) or Standard NIV (FVC below 50%) initiation. The primary outcome was time to death or tracheostomy.Trial registration number ClinicalTrials.gov: NCT01641965. RESULTS: Between May 2012 and June 2014, 42 patients were randomized to two groups, 20 to Early NIV and 22 to Standard NIV initiation. We found differences in survival in favor of the intervention group: an incidence of mortality (2.68 [1.87-5.50] vs. 3.33 [1.34-4.80] person-months) and a median survival (25.2 vs. 19.4 months), although without reaching statistical significance (p = 0.267). CONCLUSIONS: This trial did not reach the primary endpoint of survival; nevertheless, it is the first Randomized Controlled Trial (RCT) to demonstrate the benefits of early NIV in slowing the decline of respiratory muscle strength and reducing adverse events. Although not all the results reached statistical significance, all the analyzed data favor early NIV. In addition, this study demonstrates good tolerance and compliance with early NIV without quality of sleep impairment. These data reinforce the early respiratory evaluation of ALS patients and NIV initiation with an FVC of around 75%.
70Survival Prognostic Factors of Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis: A Systematic Review.PubMed
Aleksandra Orlova, Yaroslav Malygin, Anna Gofman, et al.
Life (Basel). 2024 Dec 16;14(12):1664. doi: 10.3390/life14121664.
OBJECTIVE: Amyotrophic lateral sclerosis is a neurodegenerative disease with high rates of disability and mortality. Non-invasive ventilation (NIV) is an effective method of treating patients, increasing life expectancy, but currently, predictors available to determine the best outcome of therapy in this category of patients are unknown. This systematic review aimed to determine the impact of prognostic factors on benefits from NIV application compared with non-NIV tools of treatment (invasive ventilation and standard care) in case of survival of ALS patients. METHOD: We systematically sought relevant longitudinal cohort and case-control studies published in PubMed, CINAHL/EMBASE, Cochrane library, and Scopus. RESULTS: We included seven prospective studies, published in 2010-2020, in the analysis. According to the evidence base available to date, NIV favors survival compared to non-NIV in patients with bulbar onset ALS. We obtained conflicting data on the significance of spinal onset and bulbar function. Survival depending on patient age, and also for spinal, cervical, and flail limb phenotypes during NIV therapy has not been sufficiently studied and needs further investigation. CONCLUSIONS: The studies analyzed in this review allow us to state with confidence that NIV is effective in bulbar onset ALS, taking into account recommendations for duration of ventilation and the use of the full range of symptomatic therapy, including mechanically assisted coughing. The effectiveness of NIV on severe bulbar symptoms requires further research.
71ESPEN guideline clinical nutrition in neurology.PubMed
Rosa Burgos, Irene Bretón, Emanuele Cereda, et al.
Clin Nutr. 2018 Feb;37(1):354-396. doi: 10.1016/j.clnu.2017.09.003. Epub 2017 Sep 22.
Neurological diseases are frequently associated with swallowing disorders and malnutrition. Moreover, patients with neurological diseases are at increased risk of micronutrient deficiency and dehydration. On the other hand, nutritional factors may be involved in the pathogenesis of neurological diseases. Multiple causes for the development of malnutrition in patients with neurological diseases are known including oropharyngeal dysphagia, impaired consciousness, perception deficits, cognitive dysfunction, and increased needs. The present evidence- and consensus-based guideline addresses clinical questions on best medical nutrition therapy in patients with neurological diseases. Among them, management of oropharyngeal dysphagia plays a pivotal role. The guideline has been written by a multidisciplinary team and offers 88 recommendations for use in clinical practice for amyotrophic lateral sclerosis, Parkinson's disease, stroke and multiple sclerosis.
72Effect of nutrition on neurodegenerative diseases. A systematic review.PubMed
Vittorio Emanuele Bianchi, Pomares Fredy Herrera, Rizzi Laura
Nutr Neurosci. 2021 Oct;24(10):810-834. doi: 10.1080/1028415X.2019.1681088. Epub 2019 Nov 4.
Neurodegenerative diseases are characterized by the progressive functional loss of neurons in the brain, causing cognitive impairment and motoneuron disability. Although multifactorial interactions are evident, nutrition plays an essential role in the pathogenesis and evolution of these diseases. A systematic literature search was performed, and the prevalence of studies evaluated the effect of the Mediterranean diet (MeDiet), nutritional support, EPA and DHA, and vitamins on memory and cognition impairment. The data showed that malnutrition and low body mass index (BMI) is correlated with the higher development of dementia and mortality. MeDiet, nutritional support, and calorie-controlled diets play a protective effect against cognitive decline, Alzheimer's disease (AD), Parkinson disease (PD) while malnutrition and insulin resistance represent significant risk factors. Malnutrition activates also the gut-microbiota-brain axis dysfunction that exacerbate neurogenerative process. Omega-3 and -6, and the vitamins supplementation seem to be less effective in protecting neuron degeneration. Insulin activity is a prevalent factor contributing to brain health while malnutrition correlated with the higher development of dementia and mortality.
73Nutrition and dietary supplements in motor neuron disease.PubMed
Jeffrey Rosenfeld, Amy Ellis
Phys Med Rehabil Clin N Am. 2008 Aug;19(3):573-89, x. doi: 10.1016/j.pmr.2008.03.001.
Compromised nutrition leading to weight loss is a common and significant problem in the amyotrophic lateral sclerosis (ALS) patient population. The benefit of aggressive and early nutritional therapy can profoundly influence the disease course, quality of life, and survival. This article reviews the role of nutrition, both as sustenance and treatment for patients who have ALS. Self-medication with dietary supplements has become increasingly popular within this patient population. Despite their popularity, the efficacy of these compounds has been largely unsupported by formal clinical trials. Available data will be highlighted to provide a basis upon which to advise patients requesting guidance.
74Randomised controlled trial with parallel process evaluation and health economic analysis to evaluate a nutritional management intervention, OptiCALS, for patients with amyotrophic lateral sclerosis: study protocol.PubMed
Arron Peace, David Alexander White, Gemma Hackney, et al.
BMJ Open. 2025 May 27;15(5):e096098. doi: 10.1136/bmjopen-2024-096098.
INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a devastating illness that leads to muscle weakness and death usually within around 3 years of diagnosis. People with ALS (pwALS) often lose weight due to raised energy requirements and symptoms of the disease presenting significant challenges to taking adequate oral diet, with those who lose more weight being at a greater chance of earlier death. There is also some evidence to suggest that a higher calorie diet may benefit the disease course in pwALS, but further research is needed. METHODS AND ANALYSIS: Two armed, parallel group, superiority, open labelled, randomised controlled trial, with internal pilot, to assess the effectiveness of an early high calorie diet on functional outcomes in ALS, comprising two treatment arms: (1) standard care, (2) standard care with additional active management using the OptiCALS complex intervention to achieve a high calorie diet (initially randomised 1:1, then 1:2 following a protocol amendment). Using a food first approach, pwALS will be encouraged and supported to follow a diet that meets an individualised calorie target from food before prescribing oral nutritional supplements. 259 pwALS will be recruited from up to 20 ALS centres across the United Kingdom and Ireland and followed up for a period of 12 months. Primary outcome is functional change measured over 12 months, using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. Secondary end points include measures of functional health, quality of life, calorie intake and weight, as well as time to gastrostomy and survival. A health economic analysis and process evaluation will also be undertaken. Participant recruitment is expected to complete in September 2025, and participant follow-up is expected to complete in September 2026. The results of this study are expected in March 2027. ETHICS AND DISSEMINATION: The trial was approved by Greater Manchester-North West Research Ethics Committee, reference 20/NW/0334 on 8 September 2020. We will publish the study findings in peer-reviewed academic journals and present at local, national and international conferences where possible. TRIAL REGISTRATION NUMBER: ISRCTN30588041.
75Patient, carer and healthcare professional perspectives on increasing calorie intake in Amyotrophic Lateral Sclerosis.PubMed
Elizabeth Coates, Nicolò Zarotti, Isobel Williams, et al.
Chronic Illn. 2023 Jun;19(2):368-382. doi: 10.1177/17423953211069090. Epub 2021 Dec 22.
OBJECTIVES: Research suggests that higher Body Mass Index is associated with improved survival in people with Amyotrophic Lateral Sclerosis (pwALS). Yet, understanding of the barriers and enablers to increasing calorie intake is limited. This study sought to explore these issues from the perspective of pwALS, informal carers, and healthcare professionals. METHODS: Interviews with 18 pwALS and 16 informal carers, and focus groups with 51 healthcare professionals. Data were analysed using template analysis and mapped to the COM-B model and Theoretical Domains Framework (TDF). RESULTS: All three COM-B components (Capability, Opportunity and Motivation) are important to achieving high calorie diets in pwALS. Eleven TDF domains were identified: Physical skills (ALS symptoms); Knowledge (about high calorie diets and healthy eating); Memory, attention, and decision processes (reflecting cognitive difficulties); Environmental context/resources (availability of informal and formal carers); Social influences (social aspects of eating); Beliefs about consequences (healthy eating vs. high calorie diets); Identity (interest in health lifestyles); Goals (sense of control); Reinforcement (eating habits); and Optimism and Emotion (low mood, poor appetite). DISCUSSION: To promote high calorie diets for pwALS, greater clarity around the rationale and content of recommended diets is needed. Interventions should be tailored to patient symptoms, preferences, motivations, and opportunities.
76Interventions to promote oral nutritional behaviours in people living with neurodegenerative disorders of the motor system: A systematic review.PubMed
Munira Essat, Rachel Archer, Isobel Williams, et al.
Clin Nutr. 2020 Aug;39(8):2547-2556. doi: 10.1016/j.clnu.2019.11.015. Epub 2019 Nov 19.
BACKGROUND & AIMS: Weight loss is common in people with neurodegenerative diseases of the motor system (NDMS), such as Parkinson's disease and Amyotrophic Lateral Sclerosis, and is associated with reduced quality of life, functional ability and survival. This systematic review aims to identify interventions and intervention components (i.e. behaviour change techniques [BCTs] and modes of delivery [MoDs]) that are associated with increased effectiveness in promoting oral nutritional behaviours that help people with NDMS to achieve a high calorie diet. METHODS: Eight electronic databases including MEDLINE and CINAHL were searched from inception to May 2018. All interventions from included studies were coded for relevant BCTs and MoDs. Methodological quality of studies was assessed using the Cochrane risk of bias tool. RESULTS: Fourteen studies were included. Of these, eight studies reported interventions to assist with swallowing difficulties and six studies reported interventions targeting dietary content. Beneficial effects in managing swallowing difficulties were observed with video assisted swallowing therapy, lung volume recruitment and swallowing management clinics with outpatient support. In contrast, studies reporting effectiveness of chin down posture, use of thickened liquids and respiratory muscle training were inconclusive. Positive effects in interventions targeting dietary content included the use of food pyramid tools, individualised nutritional advice with nutritional interventions, electronic health applications, face-to-face dietary counselling and high fat, high carbohydrate and milk whey protein supplements. Individualised nutritional advice with weekly phone contact did not appear to be effective. Most frequently coded BCTs were 'instructions on how to perform the behaviour', 'self-monitoring' and 'behavioural practice/rehearsal'. Most commonly identified MoDs were 'human, face-to-face' and 'somatic therapy'. However, the robustness of these findings are low due to the small number of studies, small sample sizes and large between-study variability. CONCLUSIONS: Despite the limited evidence, these findings may help inform the development of more effective interventions to promote oral nutritional behaviours in people with NDMS. However, further research is needed to demonstrate which interventions, or intervention components, yield most benefit.
77A Novel Method for Triggering the Swallowing Reflex in Patients with Amyotrophic Lateral Sclerosis: the Ishizaki Press Method.PubMed
Naohiko Ishizaki, Tomohisa Ohno, Takuya Harada, et al.
Dysphagia. 2022 Feb;37(1):177-182. doi: 10.1007/s00455-021-10261-z. Epub 2021 Feb 15.
This study describes the identification of specific maxillofacial points triggering the swallowing reflex by finger pressure in a patient with severe amyotrophic lateral sclerosis. This method has been named as the "Ishizaki Press Method." The first point was identified in a serendipitous encounter during training sessions to aid communication. This led to the search for such additional points, after obtaining informed consent from the patient and his relatives. Seven effective points were identified: the depressions in front of the left and right tragus (Ting gong points), bilateral points over the parotid and submandibular glands, and a point over the mentum in the midline of the face. The efficacy of these trigger points was noted to be ≥ 70%. The mean time taken for swallowing to occur in response to the stimulation at each of these points was less than 10 s, and the induction of a rapid swallowing reflex was recognized. Alternating left and right stimulations of the Ting gong points and the parotid points triggered the swallowing reflex significantly faster than unilateral stimulations alone. The Ishizaki Press Method may improve the management of dysphagia in patients with amyotrophic lateral sclerosis.
78Shifting Tides Toward a Proactive Patient-Centered Approach in Dysphagia Management of Neurodegenerative Disease.PubMed
Nicole M Rogus-Pulia, Emily K Plowman
Am J Speech Lang Pathol. 2020 Jul 10;29(2S):1094-1109. doi: 10.1044/2020_AJSLP-19-00136.
Purpose Persons with neurodegenerative disease frequently develop comorbid dysphagia as part of their disease process. Current "reactive" approaches to dysphagia management address dysphagia once it manifests clinically and consist of compensatory approaches. The purpose of this article is to propose a paradigm shift in dysphagia management of patients with neurodegenerative disease from a "reactive to proactive" approach by highlighting amyotrophic lateral sclerosis (ALS) and dementia as case examples. Method The authors present several areas of special consideration for speech-language pathologists (SLPs) treating dysphagia in patients with neurodegenerative disease. The drawbacks of historical "reactive" approaches to dysphagia management are described. Concepts of functional reserve for swallowing and homeostenosis are discussed. A "proactive" patient-centered paradigm of care for these patients is proposed with evidence to support its importance. A rationale for use of this approach in patients with ALS and dementia is provided with strategies for implementation. Results When treating dysphagia in patients with neurodegenerative disease, SLPs must balance a variety of factors in their decision making, including disease severity and expected progression, cultural considerations, goals of care, patient empowerment, and caregiver support. Reactive approaches to dysphagia management in these populations are problematic in that they disempower patients by focusing on use of compensatory techniques (e.g., diet modification, postural changes, feeding tube placement). Proactive approaches that employ rehabilitative interventions to increase functional reserve, such as resistance training, may result in improvement or maintenance of swallowing function longer into disease progression. An interdisciplinary team with early SLP involvement is necessary. Conclusions SLPs play a critical role in the management of dysphagia in patients with neurodegenerative disease and should be integrated early in the care of these patients. By focusing on a proactive patient-centered approach, patients with neurodegenerative conditions, such as ALS and dementia, will experience improved quality of life and health outcomes for a longer time.
79Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.PubMed
R G Miller, C E Jackson, E J Kasarskis, et al.
Neurology. 2009 Oct 13;73(15):1218-26. doi: 10.1212/WNL.0b013e3181bc0141.
OBJECTIVE: To systematically review evidence bearing on the management of patients with amyotrophic lateral sclerosis (ALS). METHODS: The authors analyzed studies from 1998 to 2007 to update the 1999 practice parameter. Topics covered in this section include slowing disease progression, nutrition, and respiratory management for patients with ALS. RESULTS: The authors identified 8 Class I studies, 5 Class II studies, and 43 Class III studies in ALS. Important treatments are available for patients with ALS that are underutilized. Noninvasive ventilation (NIV), percutaneous endoscopic gastrostomy (PEG), and riluzole are particularly important and have the best evidence. More studies are needed to examine the best tests of respiratory function in ALS, as well as the optimal time for starting PEG, the impact of PEG on quality of life and survival, and the effect of vitamins and supplements on ALS. RECOMMENDATIONS: Riluzole should be offered to slow disease progression (Level A). PEG should be considered to stabilize weight and to prolong survival in patients with ALS (Level B). NIV should be considered to treat respiratory insufficiency in order to lengthen survival (Level B) and to slow the decline of forced vital capacity (Level B). NIV may be considered to improve quality of life (Level C) [corrected].Early initiation of NIV may increase compliance (Level C), and insufflation/exsufflation may be considered to help clear secretions (Level C).
80Systematic Review of Therapeutic Physical Exercise in Patients with Amyotrophic Lateral Sclerosis over Time.PubMed
Laura Ortega-Hombrados, Guadalupe Molina-Torres, Alejandro Galán-Mercant, et al.
Int J Environ Res Public Health. 2021 Jan 26;18(3):1074. doi: 10.3390/ijerph18031074.
BACKGROUND: the main objective of this study was to analyze the potential short-, medium- and long-term effects of a therapeutic physical exercise (TFE) programme on the functionality of amyotrophic lateral sclerosis (ALS) patients, measured with the Revised Amyotrophic Lateral Sclerosis Functional Scale (ALSFRS-R) scale. METHODS: a systematic review of the PubMed, SCOPUS, Cochrane, Scientific Electronic Library Online (Scielo), Physiotherapy Evidence Database (PEDro), Cumulative Index of Nursing and Allied Health Literature (CINAHL) and Medical Literature Analysis and Retrieval System Online (MEDline) databases was carried out. The information was filtered using the following Medical Subjects Heading (MeSH) terms: "Amyotrophic lateral sclerosis", "Physical Therapy", and "Physical and Rehabilitation Medicine". The internal validity of the selected documents was evaluated using the PEDro scale. The study included clinical trials published in the last 5 years in which one of the interventions was therapeutic physical exercise in patients with ALS, using the ALSFRS-R as the main outcome variable and functional variables as secondary variables. RESULTS: 10 clinical trials were analyzed, with an internal validity of 5-7 points. The TFE groups showed significant short-, medium- and long-term differences, obtaining a mean difference of 5.8 points compared to the 7.6 points obtained by the control groups, at six months, measured with ALSFRS-R. In addition, the participants showed significant improvements in functional abilities in the short, medium and long terms. CONCLUSIONS: Therapeutic physical exercise could contribute to slowing down the deterioration of the musculature of patients with ALS, thus facilitating their performance in activities of daily living, based on the significant differences shown by these individuals in the short, medium and long term both in subjective perception, measured with ALSFRS-R, and functional capacities.
81Effects of Exercise in Patients With Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.PubMed
Lijiao Meng, Xiaoxiao Li, Cheng Li, et al.
Am J Phys Med Rehabil. 2020 Sep;99(9):801-810. doi: 10.1097/PHM.0000000000001419.
OBJECTIVE: The aim of this study was to systematically review the efficacy and safety of exercise in patients with amyotrophic lateral sclerosis (ALS). DESIGN: Randomized controlled trials of exercises for ALS were searched in PubMed, EMBASE, Web of Science, Cochrane Library, China Biology Medicine database, China National Knowledge Internet, VIP database, and Wanfang database. The primary outcomes were functional ability, pulmonary function, and quality of life. The secondary outcomes were muscle strength, fatigue and adverse events. Meta-analysis was performed using the RevMan Version 5.3 software. RESULTS: Seven randomized controlled trials including 322 patients with ALS met the inclusion criteria. Meta-analysis showed that the functional scores at long-term (standardized means difference, 0.47; 95% confidence interval, 0.08-0.86; P = 0.02) and forced vital capacity percentage predicted (mean difference, 1.71; 95% confidence interval, 0.10-3.31; P = 0.04) of patients with ALS in the exercise group were significantly higher than those in the group of no exercise or usual care. No significant difference was observed in muscle strength and quality of life. Endurance or aerobic exercise improved the functional scores of patients with ALS (standardized means difference, 0.36; 95% confidence interval, 0.04-0.68; P = 0.03). Exercise did not aggravate fatigue or result in adverse event. CONCLUSION: Exercise can significantly improve the functional ability and pulmonary function of patients with ALS safely.
82Efficacy of non-pharmacological interventions for individuals with amyotrophic lateral sclerosis: systematic review and network meta-analysis of randomized control trials.PubMed
Zhao Li, Hyunsik Kang
Sci Rep. 2024 May 18;14(1):11365. doi: 10.1038/s41598-024-62213-w.
This network meta-analysis (NMA) aimed to compare the efficacy of five non-pharmacological interventions, including exercise intervention (EI), nutritional intervention (NI), respiratory intervention (RI), psychological intervention (PSI), and integrated physical intervention (IPI), on functional status, quality of life, muscle strength, pulmonary function, and safety in patients with amyotrophic lateral sclerosis (ALS). We searched nine databases, PubMed, Cochrane, Embase, Scopus, Web of Science, CNKI, CBM, WFPD, and CSTJ, for randomized controlled trials of ALS patients. The primary outcome was the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score. Secondary outcomes were the McGill Quality of Life Questionnaire (McGill-QoL), Medical Research Council (MRC)-sum score, Forced Vital Capacity (FVC), and Fatigue Severity Scale (FSS) score. This NMA was conducted using random-effect models to calculate the standard mean difference (SMD) and 95% confidence interval (CI). All types of supplemental interventions had some benefit for patients with ALS. EI had a beneficial effect on the ALSFRS-R score (SMD: 1.01; 95% CI 0.50-1.51), FVC (SMD: 0.78; 95% CI 0.02-1.55), McGill-QoL (SMD: 0.71 95% CI 0.33-1.08), and MRC (SMD: 1.11; 95% CI 0.08-2.14). RI had a beneficial effect on the ALSFRS-R score (SMD: 0.83 95% CI 0.12-1.55). IPI had a beneficial effect on the ALSFRS-R score (SMD: 0.65 95% CI 0.06-1.24). NI had a beneficial effect on the McGill-QoL (SMD: 0.63 95% CI 0.02-1.23). The current study findings support a multimodal intervention strategy with an emphasis on EI for slowing disease progression in patients with ALS.
83An updated review on the role of prescribed exercise in the management of Amyotrophic lateral sclerosis.PubMed
Corrado Angelini, Gabriele Siciliano
Expert Rev Neurother. 2021 Aug;21(8):871-879. doi: 10.1080/14737175.2021.1951706. Epub 2021 Aug 4.
: Amyotrophic Lateral Sclerosis is a group of sporadic or familial disorders, characterized by upper and lower motor neuron involvement, with variable progression. The authors present the role of exercise in counteracting muscle disuse, particularly on limb weakness, that might antagonize denervation. The persistence of inactivity can affect many systems and the patient can develop deconditioning, muscle joint tightness, which causes contractures and pain. The main area of the review is the evaluation of the studies done on ALS exercise rehabilitation protocols, this was done by the evaluation of outcome function and patient independence exerting a positive psychological impact on both patients and caregivers. A second target is underlying differences between endurance and resistance exercise protocols, which may throw light on the biological mechanism of skeletal muscle repair, functional performance, and metabolism. The authors present not only exercise trials but also molecular biomarkers that might help define changes induced by physical rehabilitation. Our findings might help to achieve the best rehabilitation program. A standardized rehabilitation protocol is important: the instructed patients may continue therapy at home or be followed by telemedicine.: This review evaluates exercise rehabilitation, a controversial issue, evidence is weak and non-conclusive but represents the art status.
84Evidence-based position paper on Physical and Rehabilitation Medicine practice for people with amyotrophic lateral sclerosis.PubMed
Milica Lazovic, Dejan Nikolic, François C Boyer, et al.
Eur J Phys Rehabil Med. 2022 Apr;58(2):271-279. doi: 10.23736/S1973-9087.21.07120-3. Epub 2021 Nov 17.
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that affects both upper and lower motor neurons and is fatal in its course. This evidence-based position paper represents the official position of the UEMS PRM Section. The aim of the paper is to define the role of the physical and rehabilitation medicine (PRM) physician and PRM professional practice for people with ALS. A systematic review of the literature and a consensus procedure by means of a Delphi process have been performed involving the delegates of all European countries represented in the UEMS PRM Section. The systematic literature review is reported together with thirty-two recommendations resulting from the Delphi procedure. The responsibility of the PRM physician is functional assessment of persons with ALS and delivering the optimal and most effective PRM program of care. The rehabilitation program of patients with ALS should be delivered and monitored by the multiprofessional team, with the PRM physician as principal coordinator.
85Effects of a 12-week combined aerobic and strength training program in ambulatory patients with amyotrophic lateral sclerosis: a randomized controlled trial.PubMed
Alon Kalron, Ibtisam Mahameed, Israela Weiss, et al.
J Neurol. 2021 May;268(5):1857-1866. doi: 10.1007/s00415-020-10354-z. Epub 2021 Jan 3.
OBJECTIVE: To compare the effectiveness of a combined aerobic, strength, and flexibility training program with flexibility alone on disease-specific and health-related symptoms in ambulatory amyotrophic lateral sclerosis (ALS) patients. METHODS: Thirty-two ambulatory patients with ALS were equally randomized into a combined aerobic-strength intervention group or a stretching control group. The intervention period for both groups was identical, 12 consecutive weeks, two sessions per week. The combined intervention program consisted of aerobic training by recumbent cycling, flexibility achieved by stretching and passive exercises, and strength training via functional exercises. Patients in the control group performed basic stretching exercises of the upper and lower limb at home. Outcome measures included the ALS Functional Rating Scale-Revised (ALSFRS-R), respiratory function, mobility, fatigue, and quality of life and were collected 1-week prior to the intervention, after 6-weeks of training, and at the completion of the intervention. RESULTS: Twenty-eight participants (17 males, 11 females); mean age (S.D.) = 58.5 (13.2) years; mean disease duration (S.D.) = 7.3 (12.0) years, completed the study. According to the group X time analysis, significant differences were found in respiratory function, mobility, and the ALSFRS-R in favor of the aerobic-strength group. These patients maintained their abilities, whereas, a significant decrease was observed in the flexibility training group. Scores of the SF-36 categories "physical functioning", "energy fatigue" and "wellbeing" were higher following the intervention in the aerobic-strength group compared with the stretching control group. CONCLUSIONS: A 12-week combined aerobic and strength training program is far superior to flexibility alone in improving respiratory function, mobility, and wellbeing in ambulatory ALS patients.
86Dog-assisted physiotherapy in amyotrophic lateral sclerosis: a randomized controlled pilot study.PubMed
Manuela Vignolo, Riccardo Zuccarino, Romina Truffelli, et al.
Eur J Phys Rehabil Med. 2024 Jun;60(3):470-476. doi: 10.23736/S1973-9087.24.08343-6. Epub 2024 May 14.
BACKGROUND: Animal-assisted therapy (AAT) is an intervention in which the animal acts as a co-therapist. It has been mainly used in the context of patients with dementia, showing positive effects on psychological symptoms, but its potential as a physiotherapy treatment for patients with neuromuscular disorders, amyotrophic lateral sclerosis (ALS) in particular, has not yet been investigated. AIM: The aim of the study was to evaluate the impact of AAT, specifically of dog-assisted therapy, on motor functions and psychological status in patients with ALS. DESIGN: This study was a randomized controlled pilot study. SETTING: The study was carried out at the Rehabilitation Unit NEuroMuscular Omnicenter (NEMO) of Arenzano, Genoa. POPULATION: Sixty hospitalized ALS patients were enrolled. METHODS: All patients ran a regular two-weeks neurorehabilitation program twice a day. For three days a week, in place of the morning traditional treatment, the AAT group performed a rehabilitation session with a simultaneous interaction with the therapy-dog, while the control group performed a traditional rehabilitation session. The outcome measures were the Timed Up and Go Test, the Short Physical Performance Battery (SPPB), the Six Minutes Walk Test, the Ten Meters walking Test and the Hospital Anxiety and Depression Scale. RESULTS: Both groups showed an amelioration in motor scales. However, SPPB subscales as well as HADS scores showed a statistically significant improvement only in the AAT group (P values from <0.0001 to 0.0004). Additionally, across almost all motor and psychological measures, post-treatments values were significantly better for the AAT group (P values from <0.0001 to 0.01). CONCLUSIONS: The obtained results not only suggest that AAT is comparable to traditional physiotherapy treatments, but also evidence that this type of treatment has greater beneficial effects on motor and psychological symptoms in patients with ALS. CLINICAL REHABILITATION IMPACT: This study provides first evidence that AAT is a powerful rehabilitation strategy in patients with ALS, improving both motor and psychological symptoms, and therefore possibly ameliorating quality of life.
87Effects of Dog-Assisted Occupational Therapy on Upper Limb Functions in ALS and Other Neuromuscular Disorders: A Randomized Controlled Pilot Study.PubMed
Elisa Giove, Pilar Maria Ferraro, Mirela Lungu, et al.
Muscle Nerve. 2025 Nov;72(5):1122-1129. doi: 10.1002/mus.70012. Epub 2025 Sep 4.
INTRODUCTION/AIMS: The beneficial effects of animal-assisted therapy (AAT) on balance, walking endurance, and mood symptoms in amyotrophic lateral sclerosis (ALS) have been previously demonstrated. In this study, we aimed at expanding upon these findings by further evaluating its effects on upper limb (UL) functions and mood symptoms both in ALS and other neuromuscular disorders (NMDs). METHODS: Sixty-eight patients participated in a regular 2-week occupational therapy program once a day. For three days a week, in place of the traditional treatment, the AAT group (N = 34) performed a session in interaction with the therapy dog. Outcome measures included hand grip strength, manual dexterity, and mood symptoms. Differences between baseline and post-treatment values were assessed using the Wilcoxon Signed-Rank Test, and one-way analysis of covariance was used to examine between-group differences in post-treatment values, adjusting for baseline measurements. RESULTS: Both groups improved in hand grip strength (p = 0.004-0.03), whereas mood symptoms improved exclusively in the AAT group (p = 0.0003-0.03). Post-treatment values were significantly better in the AAT group (p = 0.01-0.03). When ALS patients were analyzed separately, the improvement of hand grip strength and mood symptoms was observed only in the AAT group (p = 0.001-0.04), which accordingly showed better post-treatment values (p = 0.0007-0.05). DISCUSSION: Our findings indicate that AAT has greater beneficial effects than traditional treatments on UL strength and mood symptoms. These findings have the potential to facilitate more effective rehabilitation strategies both in ALS and other NMDs.
88A randomized controlled trial of resistance and endurance exercise in amyotrophic lateral sclerosis.PubMed
Lora L Clawson, Merit Cudkowicz, Lisa Krivickas, et al.
Amyotroph Lateral Scler Frontotemporal Degener. 2018 May;19(3-4):250-258. doi: 10.1080/21678421.2017.1404108. Epub 2017 Nov 30.
OBJECTIVE: Evaluate the safety and tolerability of resistance and endurance exercise in ALS participants as measured by their ability to complete this six-month study. METHODS: Participants were randomized to Resistance, Endurance, or Stretching/Range of Motion (SROM the exercise regimen prescribed for most ALS patients) exercises. All exercises were performed at home with an individualized regimen designed by a physical therapist trained in ALS management. Primary outcome measures were tolerability of the exercises at 24 weeks defined by 50% of participants completing at least 50% of the prescribed exercise regimen. Secondary outcome measures included the ALSFRS-R, pulmonary FVC, and other measures of ALS function. RESULTS: At 12 and 24 weeks, all three exercise regimens were tolerated according to our pre-specified criteria. Compliance to the prescribed exercise regimen was the highest in the resistance and SROM arms of the study. All three forms of exercise were considered safe as there were no differences in the rates of disease progression among groups. There were no differences in the secondary outcome measures and feasibility for evaluating these measures was successful. In a post-hoc analysis, there was a trend towards fewer falls in the Resistance and Endurance groups. CONCLUSIONS: This study demonstrates that SROM, resistance, and endurance exercise are all safe to be performed with the specified regimen without any worsening of outcomes as related to ALS function. All three forms of exercise were tolerated with resistance and SROM exercises showing the highest compliance over the 24 week-period.
89Supportive and symptomatic management of amyotrophic lateral sclerosis.PubMed
Esther V Hobson, Christopher J McDermott
Nat Rev Neurol. 2016 Sep;12(9):526-38. doi: 10.1038/nrneurol.2016.111. Epub 2016 Aug 12.
The main aims in the care of individuals with amyotrophic lateral sclerosis (ALS) are to minimize morbidity and maximize quality of life. Although no cure exists for ALS, supportive and symptomatic care provided by a specialist multidisciplinary team can improve survival. The basis for supportive management is shifting from expert consensus guidelines towards an evidence-based approach, which encourages the use of effective treatments and could reduce the risk of harm caused by ineffective or unsafe interventions. For example, respiratory support using noninvasive ventilation has been demonstrated to improve survival and quality of life, whereas evidence supporting other respiratory interventions is insufficient. Increasing evidence implicates a causal role for metabolic dysfunction in ALS, suggesting that optimizing nutrition could improve quality of life and survival. The high incidence of cognitive dysfunction and its impact on prognosis is increasingly recognized, although evidence for effective treatments is lacking. A variety of strategies are used to manage the other physical and psychological symptoms, the majority of which have yet to be thoroughly evaluated. The need for specialist palliative care throughout the disease is increasingly recognized. This Review describes the current approaches to symptomatic and supportive care in ALS and outlines the current guidance and evidence for these strategies.
90The amyotrophic lateral sclerosis center: a model of multidisciplinary management.PubMed
Angeli S Mayadev, Michael D Weiss, B Jane Distad, et al.
Phys Med Rehabil Clin N Am. 2008 Aug;19(3):619-31, xi. doi: 10.1016/j.pmr.2008.04.004.
Amyotrophic lateral sclerosis (ALS) is a devastating, progressive motor neuron disorder that poses a myriad of clinical problems. Patients who have ALS are best cared for in a multidisciplinary fashion, with involvement of clinicians from various specialties, including neurology, physical medicine and rehabilitation, pulmonary medicine, clinical nurse specialists or nurse practitioners, physical and occupational therapists, speech language pathologists, dietitians, psychologists, social workers, and case managers. This article provides a summary of the current research into the rehabilitation of ALS, including the role of exercise, spasticity management, mood disorders, pain, and palliative care.
91European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).PubMed
Philip Van Damme, Ammar Al-Chalabi, Peter M Andersen, et al.
Eur J Neurol. 2024 Jun;31(6):e16264. doi: 10.1111/ene.16264. Epub 2024 Mar 12.
BACKGROUND: This update of the guideline on the management of amyotrophic lateral sclerosis (ALS) was commissioned by the European Academy of Neurology (EAN) and prepared in collaboration with the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD) and the support of the European Network for the Cure ALS (ENCALS) and the European Organization for Professionals and Patients with ALS (EUpALS). METHODS: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the effectiveness of interventions for ALS. Two systematic reviewers from Cochrane Response supported the guideline panel. The working group identified a total of 26 research questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available. RESULTS: A guideline mapping effort revealed only one other ALS guideline that used GRADE methodology (a National Institute for Health and Care Excellence [NICE] guideline). The available evidence was scarce for many research questions. Of the 26 research questions evaluated, the NICE recommendations could be adapted for 8 questions. Other recommendations required updates of existing systematic reviews or de novo reviews. Recommendations were made on currently available disease-modifying treatments, multidisciplinary care, nutritional and respiratory support, communication aids, psychological support, treatments for common ALS symptoms (e.g., muscle cramps, spasticity, pseudobulbar affect, thick mucus, sialorrhea, pain), and end-of-life management. CONCLUSIONS: This update of the guideline using GRADE methodology provides a framework for the management of ALS. The treatment landscape is changing rapidly, and further updates will be prepared when additional evidence becomes available.
92Ethical considerations and palliative care in patients with amyotrophic lateral sclerosis: A review.PubMed
V Danel-Brunaud, L Touzet, L Chevalier, et al.
Rev Neurol (Paris). 2017 May;173(5):300-307. doi: 10.1016/j.neurol.2017.03.032. Epub 2017 May 4.
Amyotrophic lateral sclerosis (ALS) is not a curable disease, but it is treatable. By definition, much of the care provided to ALS patients is palliative, even though active life-sustaining strategies are available to prolong survival. Healthcare professionals must develop communication skills that help patients cope with the inexorable progression of the disease and the inevitability of death. Symptomatic treatments as well as respiratory insufficiency and nutritional life-sustaining therapies must be regularly evaluated as the disease progresses, without losing sight of the burden placed on the patient's non-professional caregivers. The decision-making process regarding tracheostomy with invasive ventilation (TIV) is of greater complexity. Providing full information is crucial. Several long interviews are necessary to explain, discuss and allow assimilation of the information. Also, physicians should be careful not to focus exclusively on the biomedical aspects of disease, as ALS patients generally welcome the opportunity to discuss end-of-life issues with their physicians. Psychological factors, education level and cognitive status (especially the level of executive dysfunction) have a major influence on their decisions. However, as many patients do not complete advance directives with regard to TIV, advance care planning may instead be suggested in anticipation of emergency interventions. This should be discussed by healthcare professionals and the patient, and based on the wishes of the patient and caregiver(s), and communicated to all healthcare professionals. Many healthcare professionals are involved in the management of an ALS patient: they include not only those at ALS centers who provide diagnosis, follow-up and treatment initiation (particularly for respiratory and nutritional care), but also the medical and social care networks involved in disability support and home care. Specialist palliative care teams can work in partnership with ALS centers early in the course of the disease, with the center coordinating information-sharing and collaborative discussions.
93Advance directives in amyotrophic lateral sclerosis - a systematic review and meta-analysis.PubMed
Anne Lisa Mangal, Martin Mücke, Roman Rolke, et al.
BMC Palliat Care. 2024 Jul 29;23(1):191. doi: 10.1186/s12904-024-01524-1.
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motoneuron. It is associated with a life expectancy of 2-4 years after diagnosis. Individuals experience paralysis, dysphagia, respiratory failure and loss of communicative function, rendering advance care planning (ACP) critically important. This systematic review primarily aimed to internationally compare the application of advance directives (AD) and ACP in ALS. Its secondary aim was to identify ACP preferences, identify fields for future research and to generate recommendations for improving patient care through ACP. METHODS: We conducted a systematic literature review and meta-analysis. Five electronic databases (Embase, Medline, Scopus, PsycInfo and CENTRAL) were searched for qualitative and quantitative primary literature from 1999 to 2024. Cross-references were used to identify additional publications. Study selection was performed based on inclusion criteria. Number and content of AD were extracted systematically. After statistical analysis consecutive meta-analysis was performed for international differences and changes over time. Quality assessment of studies was performed using the MMAT (Mixed Methods Appraisal Tool). PROSPERO Registration (June 07, 2021) : CRD42021248040. RESULTS: A total of 998 records was screened of which 26 were included in the synthesis. An increase in publication numbers of 88.9% was observed from 1999 to 2024. Results regarding use and content of AD were heterogeneous and international differences were detected. AD were signed in 60.4% of records (1,629 / 2,696 patients). The number of AD decreased over time when separating the review period in two decades (1st 1999-2011: 78% vs. 2nd 2012-2024: 42%). Study quality was superior in qualitative and mixed method designs compared to quantitative studies. CONCLUSION: Further prospective studies should include detailed analyses on preferences regarding ventilation and artificial nutrition in ALS and should encompass countries of the global south. Despite the complexity of ACP with regard to individual patient needs, ACP should be part of each individual support plan for ALS patients and should specifically comprise a discussion on the preferred place of death. The available disease-specific AD documents should be preferred.
94Advance care planning for patients with amyotrophic lateral sclerosis.PubMed
Benjamin H Levi, Zachary Simmons, Courtney Hanna, et al.
Amyotroph Lateral Scler Frontotemporal Degener. 2017 Aug;18(5-6):388-396. doi: 10.1080/21678421.2017.1285317. Epub 2017 Mar 5.
PURPOSE: To determine whether an advance care planning (ACP) decision-aid could improve communication about end-of-life treatment wishes between patients with amyotrophic lateral sclerosis (ALS) and their clinicians. METHODS: Forty-four patients with ALS (>21, English-speaking, without dementia) engaged in ACP using an interactive computer based decision-aid. Before participants completed the intervention, and again three months later, their clinicians reviewed three clinical vignettes, and made treatment decisions (n = 18) for patients. After patients indicated their agreement with the team's decisions, concordance was calculated. RESULTS: The mean concordance between patient wishes and the clinical team decisions was significantly higher post-intervention (post = 91.9%, 95% CI = 87.8, 96.1, vs. pre = 52.4%, 95% CI = 41.9, 62.9; p <0.001). Clinical team members reported greater confidence that their decisions accurately represented each patient's wishes post-intervention (mean = 6.5) compared to pre-intervention (mean = 3.3, 1 = low, 10 = high, p <0.001). Patients reported high satisfaction (mean = 26.4, SD = 3.2; 6 = low, 30 = high) and low decisional conflict (mean = 28.8, SD = 8.2; 20 = low, 80 = high) with decisions about end-of-life care, and high satisfaction with the decision-aid (mean = 52.7, SD = 5.7, 20 = low, 60 = high). Patient knowledge regarding ACP increased post-intervention (pre = 47.8% correct responses vs. post = 66.3%; p <0.001) without adversely affecting patient anxiety or self-determination. CONCLUSION: A computer based ACP decision-aid can significantly improve clinicians' understanding of ALS patients' wishes with regard to end-of-life medical care.
95Advance Care Planning Among Patients With Amyotrophic Lateral Sclerosis: Patient Perspectives on Goals of Care Conversations.PubMed
Joel Phillips, Stacy Dixon, Tracy Koehler, et al.
Am J Hosp Palliat Care. 2024 Mar;41(3):295-301. doi: 10.1177/10499091231172901. Epub 2023 Apr 27.
INTRODUCTION: Little is known regarding circumstances surrounding advanced care planning (ACP) for patients with amyotrophic lateral sclerosis (ALS). We aim to describe preferences, and perspectives surrounding ACP in patients with ALS. METHODS: We conducted a survey of patients with ALS. Survey questions were related to advance directive completion and ACP discussions regarding end-of-life (EoL) choices. RESULTS: 49 surveys were included. Patients have given thought to advance directives, goals of care, and EoL treatments within months of diagnosis (Median: 1 month; IQR: .6 - 3 months). Twenty-seven opened dialogue with spouses, 24 with family members, 19 with health professionals and 16 with their lawyer. Eighty percent were comfortable discussing advance directives and power of attorney while fewer (70%) are less comfortable regarding specific aspects of care such as CPR or invasive ventilation. Only one barrier to discussion was identified with one patient reporting they did not wish to talk about the topic. There was no significant correlation between timing of diagnosis and whether an EoL discussion had occurred (τ = .23, P = .14: n = 42). Level of feeling informed was significantly associated with making EoL decisions for CPR, legal arrangements for a decision maker and completion of living will or AD. CONCLUSION: In this small cohort, a substantial proportion of ALS patients initiated EoL conversations early. When feeling informed, patients were more likely to make specific EoL choices. Findings suggest an opportunity for providers to help facilitate conversations, ensuring patient wishes.
96Palliative Care Issues in Amyotrophic Lateral Sclerosis: An Evidenced-Based Review.PubMed
Chafic Y Karam, Sabrina Paganoni, Nanette Joyce, et al.
Am J Hosp Palliat Care. 2016 Feb;33(1):84-92. doi: 10.1177/1049909114548719. Epub 2014 Sep 8.
As palliative care physicians become increasingly involved in the care of patients with amyotrophic lateral sclerosis (ALS), they will be asked to provide guidance regarding the use of supplements, diet, exercise, and other common preventive medicine interventions. Moreover, palliative care physicians have a crucial role assisting patients with ALS in addressing health care decisions to maximize quality of life and cope with a rapidly disabling disease. It is therefore important for palliative care physicians to be familiar with commonly encountered palliative care issues in ALS. This article provides an evidenced-based review of palliative care options not usually addressed in national and international ALS guidelines.
97Documentation of advance care planning forms in patients with amyotrophic lateral sclerosis.PubMed
Sara M Takacs, Amber R Comer
Muscle Nerve. 2022 Feb;65(2):187-192. doi: 10.1002/mus.27462. Epub 2021 Nov 30.
INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive weakness. Survival is typically only a few years from symptom onset. The often-predictable disease course creates opportunities to complete advance care planning (ACP) forms. The Physician Orders for Life-Sustaining Treatment (POLST) is a broadly used ACP paradigm to communicate end-of-life wishes but has not been well-studied in the ALS population. METHODS: In this retrospective chart review study, patients diagnosed with ALS seen between 2014 and 2018 at an academic ALS center were identified. Demographic information, clinical characteristics, and ACP data were collected. RESULTS: Of 513 patients identified, 30% had an ACP document. POLST forms were competed in 16.6% of patients with 73.8% of forms signed by a neurologist. Only 5.1% of patients saw a palliative care physician. Palliative care consultation was associated with having an POLST on file (P < .001). Patients with completed POLST forms were significantly more likely to have been seen in clinic more frequently (P < .001) and have a lower ALS Functional Rating Scale-Revised score on last visit (P = .005). DISCUSSION: Less than one third of patients with ALS completed an ACP document, and only a small percentage completed POLST forms. The data suggest a need for greater documentation of goals of care in the ALS population.
98Advance Care Planning and Healthcare Utilization in Patients With Amyotrophic Lateral Sclerosis: A Retrospective Chart Review.PubMed
Zachary Klock, Stephanie Dobak, Gail Houseman, et al.
Am J Hosp Palliat Care. 2022 Oct;39(10):1152-1156. doi: 10.1177/10499091211060011. Epub 2021 Dec 8.
: Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder resulting in functional decline and death. Despite recent emphases on advance care planning (ACP), low rates of documentation of ACP are seen in this population. : This study aims to determine rates of advance directive (AD) documentation and whether having a documented AD or ACP discussion affects healthcare utilization for ALS patients. : Retrospective chart review. : 130 patients from a multidisciplinary clinic at one U.S. tertiary care medical center. : The presence of a completed AD uploaded to the electronic medical record; the documentation of ACP discussions; and rates of percutaneous endoscopic gastrostomy (PEG) placement, tracheostomy placement, hospitalization within 2 weeks of death, death in hospital, and hospice utilization. : Overall rates of AD documentation in the electronic medical record were low at only 29.2%. Rates of PEG placement, tracheostomy placement, hospitalization within 2 weeks of death, death in hospital, and hospice utilization did not vary between patients with and without AD documentation. However, patients with a documented ACP conversation were more likely to have a PEG placed and to utilize hospice. : Our study indicates that while having a documented AD is not correlated to differences in healthcare utilization in patients with ALS, the benefit of ACP in this population is in having a dedicated conversation with patients and caregivers rather than focusing on completion of a static document.
99Palliative care in amyotrophic lateral sclerosis clinics: A survey of NEALS consortium membership.PubMed
Tejas R Mehta, Elham Bayat, Raghav Govindarajan
Muscle Nerve. 2021 May;63(5):769-774. doi: 10.1002/mus.27203. Epub 2021 Mar 6.
INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative condition managed with a multidisciplinary approach. Palliative care is important for this approach, but there is a lack of recommendations for the role and involvement of palliative medicine (PM) specialists in multidisciplinary ALS care. METHODS: This questionnaire-based survey assessed the state of palliative care in selective sites that are a part of Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS). RESULTS: Twenty-seven percent of the sites included palliative care specialists as a part of their ALS clinics and they were introduced to the patients and family by ALS specialists (75.94%) usually at an advanced stage of ALS. DISCUSSION: Our study when compared with other study results having a similar aim showed that there is a variability in the practice of palliative care specialists in ALS clinics. Having evidence-based guidelines will help in the management of ALS patients more effectively.
100[Palliative care network, six reasons for early intervention].PubMed
Odile David
Rev Infirm. 2013 Feb(188):23-4.
The benefits of early intervention on the part of a palliative care network are proven. Assisting both patients and their family, the aim is to support them through every stage of the disease. This article presents the example of the care provided by the NEPALE 91 palliative care network to a patient suffering from amyotrophic lateral sclerosis.
101Advances in molecular pathology, diagnosis, and treatment of amyotrophic lateral sclerosis.PubMed
Hristelina Ilieva, Mithila Vullaganti, Justin Kwan
BMJ. 2023 Oct 27;383:e075037. doi: 10.1136/bmj-2023-075037.
Although the past two decades have produced exciting discoveries in the genetics and pathology of amyotrophic lateral sclerosis (ALS), progress in developing an effective therapy remains slow. This review summarizes the critical discoveries and outlines the advances in disease characterization, diagnosis, imaging, and biomarkers, along with the current status of approaches to ALS care and treatment. Additional knowledge of the factors driving disease progression and heterogeneity will hopefully soon transform the care for patients with ALS into an individualized, multi-prong approach able to prevent disease progression sufficiently to allow for a dignified life with limited disability.
102Blood-based Biomarkers for Amyotrophic Lateral SclerosisPubMed
Heather M. Wilkins, Mazen M. Dimachkie, Abdulbaki Agbas
Early detection of amyotrophic lateral sclerosis (ALS) is critical for better therapeutic outcomes. The median time from symptom onset to diagnosis of ALS is 11 months, with a range of 6-21 months. Given that the median life expectancy is three years, it is important to shorten the diagnostic journey, initiate therapies promptly, and facilitate clinical research participation. Biomarkers may be the key to enhancing early diagnosis, tracking disease progression, and testing target engagement of promising therapeutics. Clinically valid biomarkers for ALS are currently lacking, and research has been ongoing to identify appropriate biomarkers. Ideal biomarkers should be minimally invasive, such as blood. In this chapter, we review our current understanding of blood-based biomarker research in ALS and discuss future directions.
103Neurofilaments as biomarkers in neurological disorders.PubMed
Michael Khalil, Charlotte E Teunissen, Markus Otto, et al.
Nat Rev Neurol. 2018 Oct;14(10):577-589. doi: 10.1038/s41582-018-0058-z.
Neuroaxonal damage is the pathological substrate of permanent disability in various neurological disorders. Reliable quantification and longitudinal follow-up of such damage are important for assessing disease activity, monitoring treatment responses, facilitating treatment development and determining prognosis. The neurofilament proteins have promise in this context because their levels rise upon neuroaxonal damage not only in the cerebrospinal fluid (CSF) but also in blood, and they indicate neuroaxonal injury independent of causal pathways. First-generation (immunoblot) and second-generation (enzyme-linked immunosorbent assay) neurofilament assays had limited sensitivity. Third-generation (electrochemiluminescence) and particularly fourth-generation (single-molecule array) assays enable the reliable measurement of neurofilaments throughout the range of concentrations found in blood samples. This technological advancement has paved the way to investigate neurofilaments in a range of neurological disorders. Here, we review what is known about the structure and function of neurofilaments, discuss analytical aspects and knowledge of age-dependent normal ranges of neurofilaments and provide a comprehensive overview of studies on neurofilament light chain as a marker of axonal injury in different neurological disorders, including multiple sclerosis, neurodegenerative dementia, stroke, traumatic brain injury, amyotrophic lateral sclerosis and Parkinson disease. We also consider work needed to explore the value of this axonal damage marker in managing neurological diseases in daily practice.
104Neurofilaments as biomarkers in neurological disorders - towards clinical application.PubMed
Michael Khalil, Charlotte E Teunissen, Sylvain Lehmann, et al.
Nat Rev Neurol. 2024 May;20(5):269-287. doi: 10.1038/s41582-024-00955-x. Epub 2024 Apr 12.
Neurofilament proteins have been validated as specific body fluid biomarkers of neuro-axonal injury. The advent of highly sensitive analytical platforms that enable reliable quantification of neurofilaments in blood samples and simplify longitudinal follow-up has paved the way for the development of neurofilaments as a biomarker in clinical practice. Potential applications include assessment of disease activity, monitoring of treatment responses, and determining prognosis in many acute and chronic neurological disorders as well as their use as an outcome measure in trials of novel therapies. Progress has now moved the measurement of neurofilaments to the doorstep of routine clinical practice for the evaluation of individuals. In this Review, we first outline current knowledge on the structure and function of neurofilaments. We then discuss analytical and statistical approaches and challenges in determining neurofilament levels in different clinical contexts and assess the implications of neurofilament light chain (NfL) levels in normal ageing and the confounding factors that need to be considered when interpreting NfL measures. In addition, we summarize the current value and potential clinical applications of neurofilaments as a biomarker of neuro-axonal damage in a range of neurological disorders, including multiple sclerosis, Alzheimer disease, frontotemporal dementia, amyotrophic lateral sclerosis, stroke and cerebrovascular disease, traumatic brain injury, and Parkinson disease. We also consider the steps needed to complete the translation of neurofilaments from the laboratory to the management of neurological diseases in clinical practice.
105Biomarkers for amyotrophic lateral sclerosis.PubMed
Simon Witzel, Kristina Mayer, Patrick Oeckl
Curr Opin Neurol. 2022 Oct 1;35(5):699-704. doi: 10.1097/WCO.0000000000001094. Epub 2022 Aug 4.
PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is an incurable, devastating neurodegenerative disease. Still, the diagnosis is mainly based on clinical symptoms, and the treatment options are strongly limited. However, the pipeline of potential treatments currently tested in clinical trials is promising. This review will discuss developments in ALS biomarker research and applications within the last 2 years and suggest future directions and needs. RECENT FINDINGS: The diagnostic and prognostic utility of neurofilaments, a general marker for axoneuronal degeneration, has been confirmed by further studies in patients with ALS, and neurofilaments are finding their way into routine diagnostic and clinical trials. Additionally, there have been advancements in developing and implementing disease-specific biomarkers, especially in patients with a genetic variant, such as SOD1 or C9orf72 . Here, biomarkers have already been used as target markers and outcome parameters for novel treatment approaches. In addition, several novel biomarkers have shown encouraging results but should be discussed in the context of their early stage of assay and clinical establishment. SUMMARY: The first biomarkers have found their way into clinical routine in ALS. In light of an increasing pipeline of potential treatments, further progress in discovering and implementing novel and existing biomarkers is crucial.
106Neurofilament light-chain response during therapy with antisense oligonucleotide tofersen in SOD1-related ALS: Treatment experience in clinical practice.PubMed
Thomas Meyer, Peggy Schumann, Patrick Weydt, et al.
Muscle Nerve. 2023 Jun;67(6):515-521. doi: 10.1002/mus.27818. Epub 2023 Apr 3.
INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations (SOD1-ALS), the antisense oligonucleotide tofersen had been investigated in a phase III study (VALOR) and subsequently introduced in an expanded access program. In this study we assess neurofilament light chain (NfL) before and during tofersen treatment. METHODS: In six SOD1-ALS patients treated with tofersen at three specialized ALS centers in Germany, NfL in cerebrospinal fluid (CSF-NfL) and/or serum (sNfL) were investigated using the ALS Functional Rating Scale Revised (ALSFRS-R) and ALS progression rate (ALS-PR), defined by monthly decline of ALSFRS-R. RESULTS: Three of the six SOD1-ALS patients reported a negative family history. Three patients harbored a homozygous c.272A > C, p.(Asp91Ala) mutation. These and two other patients showed slower progressing ALS (defined by ALS-PR <0.9), whereas one patient demonstrated rapidly progressing ALS (ALS-PR = 2.66). Mean treatment duration was 6.5 (range 5 to 8) months. In all patients, NfL decreased (mean CSF-NfL: -66%, range -52% to -86%; mean sNfL: -62%, range -36% to -84%). sNfL after 5 months of tofersen treatment was significantly reduced compared with the nearest pretreatment measurement (P = .017). ALS-PR decreased in two patients, whereas no changes in ALSFRS-R were observed in four participants who had very low ALS-PR or ALSFRS-R values before treatment. DISCUSSION: In this case series, the significant NfL decline after tofersen treatment confirmed its value as response biomarker in an expanded clinical spectrum of SOD1-ALS. Given the previously reported strong correlation between sNfL and ALS progression, the NfL treatment response supports the notion of tofersen having disease-modifying activity.
107Head-to-head comparison of four plasma neurofilament light chain (NfL) immunoassays.PubMed
Susan Ashrafzadeh-Kian, Daniel Figdore, Bethany Larson, et al.
Clin Chim Acta. 2024 Jul 15;561:119817. doi: 10.1016/j.cca.2024.119817. Epub 2024 Jun 13.
BACKGROUND: Neurofilament Light Chain (NfL) is an emerging blood biomarker of neuro-axonal injury and neurodegeneration with the potential to be used in the clinical management of various neurological conditions. Various NfL immunoassays are in development on high-throughput automated systems, but little information is available related to the comparability between assays. In this study, we performed a head-to-head comparison of four NfL immunoassays using plasma samples from individuals with various neurological conditions. METHODS: EDTA plasma samples in which NfL was ordered clinically were stratified according to diagnosis. NfL concentrations (pg/mL) in plasma were obtained using the Quanterix Simoa®, the Roche Elecsys, the Siemens Healthineers Atellica®IM, and the Fujirebio Lumipulse® NfL assays. Passing-Bablok regression analyses were performed to assess the correlation and bias between methods. Additionally, the distribution of NfL concentrations for each assay was assessed in three disease groups: amyotrophic lateral sclerosis (ALS) upon initial diagnosis, ALS treated, and multiple sclerosis (MS). RESULTS: The R between assays were all ≥ 0.95, however, significant proportional bias was observed between some assays. In particular, the Roche Elecsys assay NfL concentrations were significantly lower (∼85 %) when compared against the other three assays. The four assays were comparable with regards to the percentage of patients that were identified as having an elevated NfL result in the various clinical groups: ALS initial diagnoses (83-94 %), ALS untreated (93-100 %), and MS (8-18 %). CONCLUSIONS: This is the first study describing a head-to-head comparison of four automated NfL immunoassays. We demonstrate that there is a strong correlation between assays but a lack of standardization which is evident by the bias observed between some of the evaluated methods. These analytical differences will be important to consider when using NfL as a biomarker of neurodegeneration.
108Estimated Prevalence and Incidence of Amyotrophic Lateral Sclerosis and SOD1 and C9orf72 Genetic Variants.PubMed
Carolyn A Brown, Cathy Lally, Varant Kupelian, et al.
Neuroepidemiology. 2021;55(5):342-353. doi: 10.1159/000516752. Epub 2021 Jul 9.
INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a rare neurological disorder characterized by progressive deterioration of motor neurons. Assessment of the size/geographic distribution of the ALS population, including ALS with genetic origin, is needed to understand the burden of the disease and the need for clinical intervention and therapy. OBJECTIVES: The main objective of this study was to estimate the number of prevalent and incident ALS cases overall and superoxide dismutase 1 (SOD1) and chromosome 9 open reading frame 72 (C9orf72) ALS in 22 countries across Europe (Belgium, France, Germany, Ireland, Italy, Netherlands, Norway, Russia, Spain, Sweden, and UK), North America (USA and Canada), Latin America (Argentina, Brazil, Colombia, Mexico, and Uruguay), and Asia (China, Japan, South Korea, and Taiwan). METHODS: A comprehensive literature search was conducted to identify population-based studies reporting ALS prevalence and/or incidence rates. Pooled prevalence and incidence rates were obtained using a meta-analysis approach at the country and regional geographic level. A country-level pooled estimate was used when ≥2 studies were available per country and geographic regional pooled estimates were used otherwise. The proportion of cases with a SOD1 or C9orf72 mutation among sporadic (sALS) and familial (fALS) cases were obtained from a previous systematic review and meta-analysis. RESULTS: Pooled prevalence rates (per 100,000 persons) and incidence rates (per 100,000 person-years) were 6.22 and 2.31 for Europe, 5.20 and 2.35 for North America, 3.41 and 1.25 for Latin America, 3.01 and 0.93 for Asian countries excluding Japan, and 7.96 and 1.76 for Japan, respectively. Significant heterogeneity in reported incidence and prevalence was observed within and between countries/geographic regions. The estimated number of 2020 ALS cases across the 22 countries is 121,028 prevalent and 41,128 incident cases. The total estimated number of prevalent SOD1 cases is 2,876 cases, of which, 1,342 (47%) were fALS and 1,534 (53%) were sALS, and the number of incident SOD1 cases is 946 (434 [46%] fALS and 512 [54%] sALS). The total estimated number of prevalent C9orf72 cases is 4,545 (1,198 [26%] fALS, 3,347 [74%] sALS), and the number of incident C9orf72 cases is 1,706 (450 [26%] fALS and 1,256 [74%] sALS). DISCUSSION: The estimated number of patients with SOD1 and C9orf72 ALS suggests that although the proportions of SOD1 and C9orf72 are higher among those with fALS, the majority of SOD1 and C9orf72 ALS cases may be found among those with sALS (about 53 and 74%, respectively). These results suggest that classification of fALS based on reported family history does not capture the full picture of ALS of genetic origin.
109Genetic Epidemiology of Amyotrophic Lateral Sclerosis in Norway: A 2-Year Population-Based Study.PubMed
Cathrine Goberg Olsen, Øyvind Løvold Busk, Tori Navestad Aanjesen, et al.
Neuroepidemiology. 2022;56(4):271-282. doi: 10.1159/000525091. Epub 2022 May 16.
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons. In Europe, disease-causing genetic variants have been identified in 40-70% of familial ALS patients and approximately 5% of sporadic ALS patients. In Norway, the contribution of genetic variants to ALS has not yet been studied. In light of the potential development of personalized medicine, knowledge of the genetic causes of ALS in a population is becoming increasingly important. The present study provides clinical and genetic data on familial and sporadic ALS patients in a Norwegian population-based cohort. METHODS: Blood samples and clinical information from ALS patients were obtained at all 17 neurological departments throughout Norway during a 2-year period. Genetic analysis of the samples involved expansion analysis of C9orf72 and exome sequencing targeting 30 known ALS-linked genes. The variants were classified using genotype-phenotype correlations and bioinformatics tools. RESULTS: A total of 279 ALS patients were included in the study. Of these, 11.5% had one or several family members affected by ALS, whereas 88.5% had no known family history of ALS. A genetic cause of ALS was identified in 31 individuals (11.1%), among which 18 (58.1%) were familial and 13 (41.9%) were sporadic. The most common genetic cause was the C9orf72 expansion (6.8%), which was identified in 8 familial and 11 sporadic ALS patients. Pathogenic or likely pathogenic variants of SOD1 and TBK1 were identified in 10 familial and 2 sporadic cases. C9orf72 expansions dominated in patients from the Northern and Central regions, whereas SOD1 variants dominated in patients from the South-Eastern region. CONCLUSION: In the present study, we identified several pathogenic gene variants in both familial and sporadic ALS patients. Restricting genetic analysis to only familial cases would miss more than 40 percent of those with a disease-causing genetic variant, indicating the need for genetic analysis in sporadic cases as well.
110Current State and Future Directions in the Therapy of ALS.PubMed
Laura Tzeplaeff, Sibylle Wilfling, Maria Viktoria Requardt, et al.
Cells. 2023 May 31;12(11):1523. doi: 10.3390/cells12111523.
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder affecting upper and lower motor neurons, with death resulting mainly from respiratory failure three to five years after symptom onset. As the exact underlying causative pathological pathway is unclear and potentially diverse, finding a suitable therapy to slow down or possibly stop disease progression remains challenging. Varying by country Riluzole, Edaravone, and Sodium phenylbutyrate/Taurursodiol are the only drugs currently approved in ALS treatment for their moderate effect on disease progression. Even though curative treatment options, able to prevent or stop disease progression, are still unknown, recent breakthroughs, especially in the field of targeting genetic disease forms, raise hope for improved care and therapy for ALS patients. In this review, we aim to summarize the current state of ALS therapy, including medication as well as supportive therapy, and discuss the ongoing developments and prospects in the field. Furthermore, we highlight the rationale behind the intense research on biomarkers and genetic testing as a feasible way to improve the classification of ALS patients towards personalized medicine.
111C9orf72 BAC Mouse Model with Motor Deficits and Neurodegenerative Features of ALS/FTD.PubMed
Yuanjing Liu, Amrutha Pattamatta, Tao Zu, et al.
Neuron. 2016 May 4;90(3):521-34. doi: 10.1016/j.neuron.2016.04.005. Epub 2016 Apr 21.
To define how the C9orf72 GGGGCC expansion mutation causes ALS/FTD and to facilitate therapy development, a mouse model that recapitulates the molecular and phenotypic features of the disease is urgently needed. Two groups recently reported BAC mouse models that produce RNA foci and RAN proteins but, surprisingly, do not develop the neurodegenerative or behavioral features of ALS/FTD. We now report a BAC mouse model of C9orf72 ALS/FTD that shows decreased survival, paralysis, muscle denervation, motor neuron loss, anxiety-like behavior, and cortical and hippocampal neurodegeneration. These mice express C9orf72 sense transcripts and upregulated antisense transcripts. In contrast to sense RNA foci, antisense foci preferentially accumulate in ALS/FTD-vulnerable cell populations. RAN protein accumulation increases with age and disease, and TDP-43 inclusions are found in degenerating brain regions in end-stage animals. The ALS/FTD phenotypes in our mice provide a unique tool that will facilitate developing therapies targeting pathways that prevent neurodegeneration and increase survival.
112A case of an ALS patient with an SQSTM1 mutation - implications for the p62/NF-κB/Nrf2/autophagy pathways in the selection of individualised therapeutic strategies: a preliminary report.PubMed
Kamila Żur-Wyrozumska
Folia Med Cracov. 2025 Sep 30;65(3):173-183. doi: 10.24425/fmc.2025.156692.
INTRODUCTION: Amyotrophic lateral sclerosis (ALS) represents a heterogeneous group of neurodegenerative disorders sharing a common ALS phenotype but arising from diverse genetic and molecular mechanisms. Among the genes implicated in ALS, SQSTM1, encoding the multifunctional protein p62, plays a pivotal role in maintaining neuronal homeostasis through the regulation of autophagy and the crosstalk between NF-κB and Nrf2 pathways. Disruption of these mechanisms contributes to oxidative stress, neuroinflammation, and protein aggregation in motor neurons. MATERIAL AND METHODS: A comprehensive genetic analysis, including next-generation sequencing (NGS), whole-exome sequencing (WES), and multiplex ligation-dependent probe amplification (MLPA), was performed in a patient clinically diagnosed with ALS. Literature data regarding the role of SQSTM1, NF-κB/Nrf2 signaling, and autophagy modulation in ALS pathogenesis were reviewed to contextualize the findings. CASE PRESENTATION: We describe a 49-year-old woman with a 12-month history of progressive - bulbar-onset ALS. Genetic testing revealed a heterozygous SQSTM1 c.1175C>T (p.Pro392Leu) variant inherited from her father, classified as likely pathogenic. The patient received dimethyl fumarate (Nrf2 activator), celecoxib (NF-κB inhibitor), and rapamycin (mTOR pathway modulator) as part of an individualized treatment strategy. DISCUSSION: Mutations in SQSTM1 contribute to ALS pathogenesis through dysregulation of autophagy, impaired protein clearance, and excessive neuroinflammation mediated by NF-κB activation. The interplay between NF-κB and Nrf2 signaling pathways suggests that targeted therapeutic modulation may attenuate neurodegeneration. The patient's case illustrates the clinical and molecular heterogeneity of ALS and supports the concept of pathway-specific, precision medicine approaches. CONCLUSIONS: This case highlights the relevance of SQSTM1-related pathogenic mechanisms within the heterogeneous ALS spectrum and underscores the importance of advanced genetic testing for identifying candidates for personalized therapy.
113Amyotrophic Lateral Sclerosis: Insights and New Prospects in Disease Pathophysiology, Biomarkers and Therapies.PubMed
Jameel M Al-Khayri, Mamtha Ravindran, Akshatha Banadka, et al.
Pharmaceuticals (Basel). 2024 Oct 18;17(10):1391. doi: 10.3390/ph17101391.
Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disorder marked by the gradual loss of motor neurons, leading to significant disability and eventual death. Despite ongoing research, there are still limited treatment options, underscoring the need for a deeper understanding of the disease's complex mechanisms and the identification of new therapeutic targets. This review provides a thorough examination of ALS, covering its epidemiology, pathology, and clinical features. It investigates the key molecular mechanisms, such as protein aggregation, neuroinflammation, oxidative stress, and excitotoxicity that contribute to motor neuron degeneration. The role of biomarkers is highlighted for their importance in early diagnosis and disease monitoring. Additionally, the review explores emerging therapeutic approaches, including inhibitors of protein aggregation, neuroinflammation modulators, antioxidant therapies, gene therapy, and stem cell-based treatments. The advantages and challenges of these strategies are discussed, with an emphasis on the potential for precision medicine to tailor treatments to individual patient needs. Overall, this review aims to provide a comprehensive overview of the current state of ALS research and suggest future directions for developing effective therapies.
114Mesenchymal Stromal Cell Therapies for Neurodegenerative Diseases.PubMed
Nathan P Staff, David T Jones, Wolfgang Singer
Mayo Clin Proc. 2019 May;94(5):892-905. doi: 10.1016/j.mayocp.2019.01.001.
Mesenchymal stromal cells are multipotent cells that are being used to treat a variety of medical conditions. Over the past decade, there has been considerable excitement about using MSCs to treat neurodegenerative diseases, which are diseases that are typically fatal and without other robust therapies. In this review, we discuss the proposed MSC mechanisms of action in neurodegenerative diseases, which include growth factor secretion, exosome secretion, and attenuation of neuroinflammation. We then provide a summary of preclinical and early clinical work on MSC therapies in amyotrophic lateral sclerosis, multiple system atrophy, Parkinson disease, and Alzheimer disease. Continued rigorous and controlled studies of MSC therapies will be critical in order to establish efficacy and protect patients from possible untoward effects.
115Advances, Challenges, and Perspectives in Translational Stem Cell Therapy for Amyotrophic Lateral Sclerosis.PubMed
Elena Abati, Nereo Bresolin, Giacomo Comi, et al.
Mol Neurobiol. 2019 Oct;56(10):6703-6715. doi: 10.1007/s12035-019-1554-x. Epub 2019 Mar 26.
Finding an effective therapeutic approach is a primary goal for current and future research for amyotrophic lateral sclerosis (ALS), a fatal neurological disease characterized by degeneration and loss of upper and lower motor neurons. Transplantation approaches based on stem cells have been attempted in virtue of their potential to contrast simultaneously different ALS pathogenic aspects including either the replacement of lost cells or the protection of motor neurons from degeneration and toxic microenvironment. Here, we critically review the recent translational research aimed at the assessment of stem cell transplantation safety and feasibility in the treatment of ALS. Most of these efforts aim to exert a neuroprotective action rather than cell replacement. Critical aspects that emerge in these studies are the need for the identification of the most effective therapeutic cell source (mesenchymal stem cells, immune, or neural stem cells), the definition of the optimal injection site (cortical area, spinal cord, or muscles) with a suitable administration protocol (local or systemic injection), and the analysis of therapeutic mechanisms, which are necessary steps in order to overcome the hurdles posed by previous in vivo human studies. New perspectives will also be offered by the increasing number of induced pluripotent stem cell-based therapies that are now being tested in clinical trials. A thorough analysis of recently completed trials is the foundation for continued progress in cellular therapy for ALS and other neurodegenerative disorders.
116Mesenchymal stem cells for the treatment of neurodegenerative disease.PubMed
Nanette Joyce, Geralyn Annett, Louisa Wirthlin, et al.
Regen Med. 2010 Nov;5(6):933-46. doi: 10.2217/rme.10.72.
Mesenchymal stem cells/marrow stromal cells (MSCs) present a promising tool for cell therapy, and are currently being tested in US FDA-approved clinical trials for myocardial infarction, stroke, meniscus injury, limb ischemia, graft-versus-host disease and autoimmune disorders. They have been extensively tested and proven effective in preclinical studies for these and many other disorders. There is currently a great deal of interest in the use of MSCs to treat neurodegenerative diseases, in particular for those that are fatal and difficult to treat, such as Huntington's disease and amyotrophic lateral sclerosis. Proposed regenerative approaches to neurological diseases using MSCs include cell therapies in which cells are delivered via intracerebral or intrathecal injection. Upon transplantation into the brain, MSCs promote endogenous neuronal growth, decrease apoptosis, reduce levels of free radicals, encourage synaptic connection from damaged neurons and regulate inflammation, primarily through paracrine actions. MSCs transplanted into the brain have been demonstrated to promote functional recovery by producing trophic factors that induce survival and regeneration of host neurons. Therapies will capitalize on the innate trophic support from MSCs or on augmented growth factor support, such as delivering brain-derived neurotrophic factor or glial-derived neurotrophic factor into the brain to support injured neurons, using genetically engineered MSCs as the delivery vehicles. Clinical trials for MSC injection into the CNS to treat traumatic brain injury and stroke are currently ongoing. The current data in support of applying MSC-based cellular therapies to the treatment of neurodegenerative disorders are discussed.
117Stem cells therapy for ALS.PubMed
Letizia Mazzini, Angelo Vescovi, Roberto Cantello, et al.
Expert Opin Biol Ther. 2016;16(2):187-99. doi: 10.1517/14712598.2016.1116516. Epub 2016 Jan 9.
INTRODUCTION: Despite knowledge on the molecular basis of amyotrophic lateral sclerosis (ALS) having quickly progressed over the last few years, such discoveries have not yet translated into new therapeutics. With the advancement of stem cell technologies there is hope for stem cell therapeutics as novel treatments for ALS. AREAS COVERED: We discuss in detail the therapeutic potential of different types of stem cells in preclinical and clinical works. Moreover, we address many open questions in clinical translation. EXPERT OPINION: SC therapy is a potentially promising new treatment for ALS and the need to better understand how to develop cell-based experimental treatments, and how to implement them in clinical trials, becomes more pressing. Mesenchymal stem cells and neural fetal stem cells have emerged as safe and potentially effective cell types, but there is a need to carry out appropriately designed experimental studies to verify their long-term safety and possibly efficacy. Moreover, the cost-benefit analysis of the results must take into account the quality of life of the patients as a major end point. It is our opinion that a multicenter international clinical program aime d at fine-tuning and coordinating transplantation procedures and protocols is mandatory.
118Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease.PubMed
S Fadilah Abdul Wahid, Zhe Kang Law, Nor Azimah Ismail, et al.
Cochrane Database Syst Rev. 2019 Dec 19;12(12):CD011742. doi: 10.1002/14651858.CD011742.pub3.
BACKGROUND: Amyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND), is a fatal disease associated with rapidly progressive disability, for which no definitive treatment exists. Current treatment approaches largely focus on relieving symptoms to improve the quality of life of those affected. The therapeutic potential of cell-based therapies in ALS/MND has not been fully evaluated, given the paucity of high-quality clinical trials. Based on data from preclinical studies, cell-based therapy is a promising treatment for ALS/MND. This review was first published in 2015 when the first clinical trials of cell-based therapies were still in progress. We undertook this update to incorporate evidence now available from randomised controlled trials (RCTs). OBJECTIVES: To assess the effects of cell-based therapy for people with ALS/MND, compared with placebo or no treatment. SEARCH METHODS: On 31 July 2019, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, and Embase. We also searched two clinical trials registries for ongoing or unpublished studies. SELECTION CRITERIA: We included RCTs that assigned people with ALS/MND to receive cell-based therapy versus a placebo or no additional treatment. Co-interventions were allowed, provided that they were given to each group equally. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. MAIN RESULTS: Two RCTs involving 112 participants were eligible for inclusion in this review. One study compared autologous bone marrow-mesenchymal stem cells (BM-MSC) plus riluzole versus control (riluzole only), while the other study compared combined intramuscular and intrathecal administration of autologous mesenchymal stem cells secreting neurotrophic factors (MSC-NTF) to placebo. The latter study was reported as an abstract and provided no numerical data. Both studies were funded by biotechnology companies. The only study that contributed to the outcome data in the review involved 64 participants, comparing BM-MSC plus riluzole versus control (riluzole only). It reported outcomes after four to six months. It had a low risk of selection bias, detection bias and reporting bias, but a high risk of performance bias and attrition bias. The certainty of evidence was low for all major efficacy outcomes, with imprecision as the main downgrading factor, because the range of plausible estimates, as shown by the 95% confidence intervals (CIs), encompassed a range that would likely result in different clinical decisions. Functional impairment, expressed as the mean change in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score from baseline to six months after cell injection was slightly reduced (better) in the BM-MSC group compared to the control group (mean difference (MD) 3.38, 95% CI 1.22 to 5.54; 1 RCT, 56 participants; low-certainty evidence). ALSFRS-R has a range from 48 (normal) to 0 (maximally impaired); a change of 4 or more points is considered clinically important. The trial did not report outcomes at 12 months. There was no clear difference between the BM-MSC and the no treatment group in change in respiratory function (per cent predicted forced vital capacity; FVC%; MD -0.53, 95% CI -5.37 to 4.31; 1 RCT, 56 participants; low-certainty evidence); overall survival at six months (risk ratio (RR) 1.07, 95% CI 0.94 to 1.22; 1 RCT, 64 participants; low-certainty evidence); risk of total adverse events (RR 0.86, 95% CI 0.62 to 1.19; 1 RCT, 64 participants; low-certainty evidence) or serious adverse events (RR 0.47, 95% CI 0.13 to 1.72; 1 RCT, 64 participants; low-certainty evidence). The study did not measure muscle strength. AUTHORS' CONCLUSIONS: Currently, there is a lack of high-certainty evidence to guide practice on the use of cell-based therapy to treat ALS/MND. Uncertainties remain as to whether this mode of therapy is capable of restoring muscle function, slowing disease progression, and improving survival in people with ALS/MND. Although one RCT provided low-certainty evidence that BM-MSC may slightly reduce functional impairment measured on the ALSFRS-R after four to six months, this was a small phase II trial that cannot be used to establish efficacy. We need large, prospective RCTs with long-term follow-up to establish the efficacy and safety of cellular therapy and to determine patient-, disease- and cell treatment-related factors that may influence the outcome of cell-based therapy. The major goals of future research are to determine the appropriate cell source, phenotype, dose and method of delivery, as these will be key elements in designing an optimal cell-based therapy programme for people with ALS/MND. Future research should also explore novel treatment strategies, including combinations of cellular therapy and standard or novel neuroprotective agents, to find the best possible approach to prevent or reverse the neurological deficit in ALS/MND, and to prolong survival in this debilitating and fatal condition.
119Neural Stem/Progenitor Cell Therapy in Patients and Animals with Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-analysis.PubMed
Jinyu Zhang, Ruiyun Guo, Zijing Zhou, et al.
Mol Neurobiol. 2025 May;62(5):6521-6536. doi: 10.1007/s12035-024-04682-8. Epub 2025 Jan 16.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative malady that causes progressive degeneration and loss of motor neuron function in the brain and spinal cord, eventually resulting in muscular atrophy, paralysis, and death. Neural stem/progenitor cell (NSPC) transplantation can improve bodily function in animals and delay disease progression in patients with ALS. This paper summarizes and analyzes the efficacy and safety of neural stem/progenitor cell (NSPC) transplantation as a treatment for ALS, aiming to improve function and delay disease progression in patients. We present a summary of the pathogenic mechanism and causative genes associated with ALS and describe the mechanism and efficacy of NSPC treatment for ALS. We comprehensively searched for relevant English-language articles published between January 1, 2000 and October 1, 2023, across the following five medical databases: PubMed, EMBASE, OVID, Web of Science, and the Cochrane Library. We examined experimental indices of physical function in animals and patients who underwent stem cell transplantation. All statistical analyses were performed via Review Manager 5.4. The study comprised a total of 16 investigations, including 5 clinical studies and 11 animal studies and involving 66 patients and 203 animals. The meta-analysis revealed that the administration of NSPCs appeared to yield positive outcomes in clinical patients, as assessed by the ALS functional rating scale and forced vital capacity. Furthermore, improvements following cell injection were observed in the rotarod test results, the Basso-Beattie-Bresnahan Locomotor Rating Scale score, weight, and survival time. Our meta-analysis, which was grounded in randomized controlled trials, revealed that the transplantation of neural stem/progenitor cells (NSPCs), has potential effects on ALS patients, enhancing the physical function of animals and mitigating degenerative effects in individuals. These underscored the promise of NSPC therapy as a viable treatment option. We report that the transplantation of neural stem/progenitor cells (NSPCs) is promising for enhancing bodily function and slowing the progression of ALS in affected patients. In this review, we summarize the treatment of ALS with NSPCs, evaluating both its efficacy and safety. Through database searches, we identified 16 studies involving 66 patients and 203 animals and analyzed the experimental indices of physical function following stem cell transplantation. The meta-analysis results indicated a positive impact of NSPCs on the clinical conditions of patients and the behavior of animals. A meta-analysis of randomized controlled trials further supported the conclusion that NSPC transplantation has a beneficial effect on improving physical function and mitigating degeneration in ALS patients.
120Pharmacokinetic characteristics of mesenchymal stem cells in translational challenges.PubMed
Yunlong Shan, Mengying Zhang, Enxiang Tao, et al.
Signal Transduct Target Ther. 2024 Sep 13;9(1):242. doi: 10.1038/s41392-024-01936-8.
Over the past two decades, mesenchymal stem/stromal cell (MSC) therapy has made substantial strides, transitioning from experimental clinical applications to commercial products. MSC therapies hold considerable promise for treating refractory and critical conditions such as acute graft-versus-host disease, amyotrophic lateral sclerosis, and acute respiratory distress syndrome. Despite recent successes in clinical and commercial applications, MSC therapy still faces challenges when used as a commercial product. Current detection methods have limitations, leaving the dynamic biodistribution, persistence in injured tissues, and ultimate fate of MSCs in patients unclear. Clarifying the relationship between the pharmacokinetic characteristics of MSCs and their therapeutic effects is crucial for patient stratification and the formulation of precise therapeutic regimens. Moreover, the development of advanced imaging and tracking technologies is essential to address these clinical challenges. This review provides a comprehensive analysis of the kinetic properties, key regulatory molecules, different fates, and detection methods relevant to MSCs and discusses concerns in evaluating MSC druggability from the perspective of integrating pharmacokinetics and efficacy. A better understanding of these challenges could improve MSC clinical efficacy and speed up the introduction of MSC therapy products to the market.
121CRISPR/Cas9-Mediated Gene Correction to Understand ALS.PubMed
Yeomin Yun, Yoon Ha
Int J Mol Sci. 2020 May 27;21(11):3801. doi: 10.3390/ijms21113801.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the death of motor neurons in the spinal cord and brainstem. ALS has a diverse genetic origin; at least 20 genes have been shown to be related to ALS. Most familial and sporadic cases of ALS are caused by variants of the , , and TARDBP genes. Genome editing using clustered regularly interspaced short palindromic repeats/CRISPR-associated system 9 (CRISPR/Cas9) can provide insights into the underlying genetics and pathophysiology of ALS. By correcting common mutations associated with ALS in animal models and patient-derived induced pluripotent stem cells (iPSCs), CRISPR/Cas9 has been used to verify the effects of ALS-associated mutations and observe phenotype differences between patient-derived and gene-corrected iPSCs. This technology has also been used to create mutations to investigate the pathophysiology of ALS. Here, we review recent studies that have used CRISPR/Cas9 to understand the genetic underpinnings of ALS.
123Targets and Gene Therapy of ALS (Part 1).PubMed
Olga Shiryaeva, Christina Tolochko, Tatiana Alekseeva, et al.
Int J Mol Sci. 2025 Apr 25;26(9):4063. doi: 10.3390/ijms26094063.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons, which causes muscle atrophy. Genetic forms of ALS are recorded only in 10% of cases. However, over the past decade, studies in genetics have substantially contributed to our understanding of the molecular mechanisms underlying ALS. The identification of key mutations such as , , , and has led to the development of targeted therapy that is gradually being introduced into clinical trials, opening up a broad range of opportunities for correcting these mutations. In this review, we aimed to present an extensive overview of the currently known mechanisms of motor neuron degeneration associated with mutations in these genes and also the gene therapy methods for inhibiting the expression of their mutant proteins. Among these, antisense oligonucleotides, RNA interference (siRNA and miRNA), and gene-editing (CRISPR/Cas9) methods are of particular interest. Each has shown its efficacy in animal models when targeting mutant genes, whereas some of them have proven to be efficient in human clinical trials.
124CRISPR/cas genome editing for neurodegenerative diseases: Mechanisms, therapeutic advances, and clinical prospects.PubMed
Kalpana Pandya, Devendra Kumar
Ageing Res Rev. 2026 Jan;113:102922. doi: 10.1016/j.arr.2025.102922. Epub 2025 Oct 17.
Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Spinocerebral Ataxia (SCA), and Huntington's disease (HD) are major global health challenges. Current treatments are only symptomatic and do not address the underlying pathogenic genetic mechanisms. The development of the CRISPR/Cas genome editing technologies, has increased possibilities for targeted repair of pathological mutations. CRISPR/Cas9, Cas12, and Cas13 systems enable targeted editing and transcriptome modulation in various preclinical models. CRISPR/Cas9 disruption of mutant APP, Tau, and LRRK2 genes, reducing toxic protein aggregration in AD models has restored normal genetic function. While correction of CAG nucleotide repeats in HD, and reduction of alpha-synuclein expression in PD. RNA targeting systems like Cas13 offers additional therapeutics potential by selectively degrading disease assciated transcript without altering genomic DNA. Advancements in engineered Cas variants with enhanced specificity, such as SpCas9-HF1, base editors and prime editors, with innovative delivery strategies including adeno-associated virus (AAVs) and nanoparticle-based systems, have improved genome editing. However, challenges remain, including off-target effects, mosaicism, and delivery across the BBB, and long-term safety. Ethical consideration focuses on somatic versus germline editing, equitable access, and regulatory oversight. While somatic editing shows acceptance in treating neurological disorders. Germline interventions face strict regulations due to potential multigeneration impacts. Collectively, these technologies are the vanguard of precision molecular medicine, advancing from symptom management towards potentially curative gene therapies for neurological disorders.
125Treating neuromuscular diseases: unveiling gene therapy breakthroughs and pioneering future applications.PubMed
Yu-Fu Wu, Jun-An Chen, Yuh-Jyh Jong
J Biomed Sci. 2025 Feb 21;32(1):30. doi: 10.1186/s12929-025-01123-z.
In this review, we highlight recent advancements in adeno-associated virus (AAV)-based gene therapy for genetic neuromuscular diseases (NMDs), focusing on spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). We discuss the current FDA-approved gene therapies for NMDs and provide updates on preclinical studies that demonstrate the potential of various AAV-based gene therapies to reduce SMA severity and serve as effective treatments for DMD. Additionally, we explore the transformative impact of CRISPR/Cas9 technology on the future of gene therapy for NMDs. Despite these encouraging developments, further research is required to identify robust biomarkers that can guide treatment decisions and predict outcomes. Overall, these pioneering advancements in AAV-based gene therapy lay the groundwork for future efforts aimed at curing genetic NMDs and offer a roadmap for developing gene therapies for other neurodegenerative diseases.